6-5 FUSED RINGS AS C5a INHIBITORS

ABSTRACT

or pharmaceutically acceptable salts thereof that are modulators of the C5a receptor. Also provided are pharmaceutical compositions and methods of use including the treatment of diseases or disorders involving pathologic activation from C5a and non-pharmaceutical applications.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is an applicating claiming benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62/513,010 filed on May 31,2017, which is herein incorporated by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

NOT APPLICABLE

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

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BACKGROUND OF THE INVENTION

The complement system plays a central role in the clearance of immunecomplexes and in immune responses to infectious agents, foreignantigens, virus infected cells and tumor cells. Inappropriate orexcessive activation of the complement system can lead to harmful, andeven potentially life-threatening consequences due to severeinflammation and resulting tissue destruction. These consequences areclinically manifested in various disorders including septic shock;myocardial, as well as, intestinal ischemia/reperfusion injury; graftrejection; organ failure; nephritis; pathological inflammation; andautoimmune diseases.

The complement system is composed of a group of proteins that arenormally present in the serum in an inactive state. Activation of thecomplement system encompasses mainly three distinct pathways, i.e., theclassical, the alternative, and the lectin pathway (V. M. Holers, InClinical Immunology: Principles and Practice, ed. R. R. Rich, MosbyPress; 1996, 363-391): 1) The classical pathway is acalcium/magnesium-dependent cascade, which is normally activated by theformation of antigen-antibody complexes. It can also be activated in anantibody-independent manner by the binding of C-reactive protein,complexed with ligand, and by many pathogens including gram-negativebacteria. 2) The alternative pathway is a magnesium-dependent cascadewhich is activated by deposition and activation of C3 on certainsusceptible surfaces (e.g. cell wall polysaccharides of yeast andbacteria, and certain biopolymer materials). 3) The lectin pathwayinvolves the initial binding of mannose-binding lectin and thesubsequent activation of C2 and C4, which are common to the classicalpathway (Matsushita, M. et al., J. Exp. Med. 176: 1497-1502 (1992);Suankratay, C. et al., J. Immunol. 160: 3006-3013 (1998)).

The activation of the complement pathway generates biologically activefragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxinsand C5b-9 membrane attack complexes (MAC), all which mediateinflammatory responses by affecting leukocyte chemotaxis; activatingmacrophages, neutrophils, platelets, mast cells and endothelial cells;and increasing vascular permeability, cytolysis and tissue injury.

Complement C5a is one of the most potent proinflammatory mediators ofthe complement system. (The anaphylactic C5a peptide is 100 times morepotent, on a molar basis, in eliciting inflammatory responses than C3a.)C5a is the activated form of C5 (190 kD, molecular weight). C5a ispresent in human serum at approximately 80 μg/ml (Kohler, P. F. et al.,J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptidechains, α and β, with approximate molecular weights of 115 kD and 75 kD,respectively (Tack, B. F. et al., Biochemistry 18: 1490-1497 (1979)).Biosynthesized as a single-chain promolecule, C5 is enzymaticallycleaved into a two-chain structure during processing and secretion.After cleavage, the two chains are held together by at least onedisulphide bond as well as noncovalent interactions (Ooi, Y. M. et al.,J. Immunol. 124: 2494-2498(1980)).

C5 is cleaved into the C5a and C5b fragments during activation of thecomplement pathways. The convertase enzymes responsible for C5activation are multi-subunit complexes of C4b, C2a, and C3b for theclassical pathway and of (C3b)₂, Bb, and P for the alternative pathway(Goldlust, M. B. et al., J. Immunol. 113: 998-1007 (1974); Schreiber, R.D. et al, Proc. Natl. Acad. Sci. 75: 3948-3952 (1978)). C5 is activatedby cleavage at position 74-75 (Arg-Leu) in the α-chain. Afteractivation, the 11.2 kD, 74 amino acid peptide C5a from theamino-terminus portion of the α-chain is released. Both C5a and C3a arepotent stimulators of neutrophils and monocytes (Schindler, R. et al.,Blood 76: 1631-1638 (1990); Haeffner-Cavaillon, N. et al., J. Immunol.138: 794-700 (1987); Cavaillon, J. M. et al., Eur. J. Immunol. 20:253-257 (1990)).

In addition to its anaphylatoxic properties, C5a induces chemotacticmigration of neutrophils (Ward, P. A. et al., J. Immunol. 102: 93-99(1969)), eosinophils (Kay, A. B. et al., Immunol. 24: 969-976 (1973)),basophils (Lett-Brown, M. A. et al., J. Immunol. 117: 246-252 1976)),and monocytes (Snyderman, R. et al., Proc. Soc. Exp. Biol. Med. 138:387-390 1971)). Both C5a and C5b-9 activate endothelial cells to expressadhesion molecules essential for sequestration of activated leukocytes,which mediate tissue inflammation and injury (Foreman, K. E. et al., J.Clin. Invest. 94: 1147-1155 (1994); Foreman, K. E. et al., Inflammation20: 1-9 (1996); Rollins, S. A. et al., Transplantation 69: 1959-1967(2000)). C5a also mediates inflammatory reactions by causing smoothmuscle contraction, increasing vascular permeability, inducing basophiland mast cell degranulation and inducing release of lysosomal proteasesand oxidative free radicals (Gerard, C. et al., Ann. Rev. Immunol. 12:775-808 (1994)). Furthermore, C5a modulates the hepatic acute-phase geneexpression and augments the overall immune response by increasing theproduction of TNF-α, IL-1β, IL-6, IL-8, prostaglandins and leukotrienes(Lambris, J. D. et al., In: The Human Complement System in Health andDisease, Volanakis, J. E. ed., Marcel Dekker, New York, pp. 83-118).

The anaphylactic and chemotactic effects of C5a are believed to bemediated through its interaction with the C5a receptor. The human C5areceptor (C5aR) is a 52 kD membrane bound G protein-coupled receptor,and is expressed on neutrophils, monocytes, basophils, eosinophils,hepatocytes, lung smooth muscle and endothelial cells, and renalglomerular tissues (Van-Epps, D. E. et al., J. Immunol. 132: 2862-2867(1984); Haviland, D. L. et al., J. Immunol. 154:1861-1869 (1995);Wetsel, R. A., Immunol. Leff. 44: 183-187 (1995); Buchner, R. R. et al.,J. Immunol. 155: 308-315 (1995); Chenoweth, D. E. et al., Proc. Natl.Acad. Sci. 75: 3943-3947 (1978); Zwirner, J. et al., Mol. Immunol.36:877-884 (1999)). The ligand-binding site of C5aR is complex andconsists of at least two physically separable binding domains. One bindsthe C5a amino terminus (amino acids 1-20) and disulfide-linked core(amino acids 21-61), while the second binds the C5a carboxy-terminal end(amino acids 62-74) (Wetsel, R. A., Curr. Opin. Immunol. 7: 48-53(1995)).

C5a plays important roles in inflammation and tissue injury. Incardiopulmonary bypass and hemodialysis, C5a is formed as a result ofactivation of the alternative complement pathway when human blood makescontact with the artificial surface of the heart-lung machine or kidneydialysis machine (Howard, R. J. et al., Arch. Surg. 123: 1496-1501(1988); Kirklin, J. K. et al., J. Cardiovasc. Surg. 86: 845-857 (1983);Craddock, P. R. et al., N. Engl. J. Med. 296: 769-774 (1977)). C5acauses increased capillary permeability and edema, bronchoconstriction,pulmonary vasoconstriction, leukocyte and platelet activation andinfiltration to tissues, in particular the lung (Czermak, B. J. et al.,J Leukoc. Biol. 64: 40-48 (1998)). Administration of an anti-C5amonoclonal antibody was shown to reduce cardiopulmonary bypass andcardioplegia-induced coronary endothelial dysfunction (Tofukuji, M. etal., J. Thorac. Cardiovasc. Surg. 116: 1060-1068 (1998)).

C5a is also involved in acute respiratory distress syndrome (ARDS),Chronic Obstructive Pulmonary Disorder (COPD) and multiple organ failure(MOF) (Hack, C. E. et al., Am. J. Med. 1989: 86: 20-26; Hammerschmidt DE et al. Lancet 1980; 1: 947-949; Heideman M. et al. J. Trauma 1984; 4:1038-1043; Marc, M M, et al., Am. J. Respir. Cell and Mol. Biol., 2004:31: 216-219). C5a augments monocyte production of two importantpro-inflammatory cytokines, TNF-α and IL-1. C5a has also been shown toplay an important role in the development of tissue injury, andparticularly pulmonary injury, in animal models of septic shock(Smedegard G et al. Am. J. Pathol. 1989; 135: 489-497; Markus, S., etal., FASEB Journal (2001), 15: 568-570). In sepsis models using rats,pigs and non-human primates, anti-C5a antibodies administered to theanimals before treatment with endotoxin or E. coli resulted in decreasedtissue injury, as well as decreased production of IL-6 (Smedegard, G. etal., Am. J. Pathol. 135: 489-497 (1989); Hopken, U. et al., Eur. J.Immunol. 26: 1103-1109 (1996); Stevens, J. H. et al., J. Clin. Invest.77: 1812-1816 (1986)). More importantly, blockade or C5a with anti-C5apolyclonal antibodies has been shown to significantly improve survivalrates in a caecal ligation/puncture model of sepsis in rats (Czermak, B.J. et al., Nat. Med. 5: 788-792 (1999)). This model share many aspectsof the clinical manifestation of sepsis in humans. (Parker, S. J. etal., Br. J. Surg. 88: 22-30 (2001)). In the same sepsis model, anti-C5aantibodies were shown to inhibit apoptosis of thymocytes (Guo, R. F. etal., J. Clin. Invest. 106: 1271-1280 (2000)) and prevent MOF(Huber-Lang, M. et al., J. Immunol. 166: 1193-1199 (2001)). Anti-C5aantibodies were also protective in a cobra venom factor model of lunginjury in rats, and in immune complex-induced lung injury (Mulligan, M.S. et al. J. Clin. Invest. 98: 503-512 (1996)). The importance of C5a inimmune complex-mediated lung injury was later confirmed in mice (Bozic,C. R. et al., Science 26: 1103-1109 (1996)).

C5a is found to be a major mediator in myocardial ischemia-reperfusioninjury. Complement depletion reduced myocardial infarct size in mice(Weisman, H. F. et al., Science 249: 146-151 (1990)), and treatment withanti-C5a antibodies reduced injury in a rat model of hindlimbischemia-reperfusion (Bless, N. M. et al., Am. J. Physiol. 276: L57-L63(1999)). Reperfusion injury during myocardial infarction was alsomarkedly reduced in pigs that were retreated with a monoclonal anti-C5aIgG (Amsterdam, E. A. et al., Am. J. Physiol. 268:H448-H457 (1995)). Arecombinant human C5aR antagonist reduces infarct size in a porcinemodel of surgical revascularization (Riley, R. D. et al., J. Thorac.Cardiovasc. Surg. 120: 350-358 (2000)).

C5a driven neutrophils also contribute to many bullous diseases (e.g.,bullous pemphigoid, pemphigus vulgaris and pemphigus foliaceus). Theseare chronic and recurring inflammatory disorders clinicallycharacterized by sterile blisters that appear in the sub-epidermal spaceof the skin and mucosa. While autoantibodies to keratinocytes located atthe cutaneous basement membranes are believed to underlie the detachmentof epidermal basal keratinocytes from the underlying basement membrane,blisters are also characterized by accumulation of neutrophils in boththe upper dermal layers and within the blister cavities. In experimentalmodels a reduction of neutrophils or absence of complement (total orCS-selective) can inhibit formation of sub-epidermal blisters, even inthe presence of high auto-antibody titers.

Complement levels are elevated in patients with rheumatoid arthritis(Jose, P. J. et al., Ann. Rheum. Dis. 49: 747-752 (1990); Grant, E. P.,et al., J. of Exp. Med., 196(11): 1461-1471, (2002)), lupus nephritis(Bao, L., et al., Eur. J. of Immunol., 35(8), 2496-2506, (2005)) andsystemic lupus erythematosus (SLE) (Porcel, J. M. et al., Clin. Immunol.Immunopathol. 74: 283-288 (1995)). C5a levels correlate with theseverity of the disease state. Collagen-induced arthritis in mice andrats resembles the rheumatoid arthritic disease in human. Mice deficientin the C5a receptor demonstrated a complete protection from arthritisinduced by injection of monoclonal anti-collagen Abs (Banda, N. K., etal., J. of Immunol., 2003, 171: 2109-2115). Therefore, inhibition of C5aand/or C5a receptor (C5aR) could be useful in treating these chronicdiseases.

The complement system is believed to be activated in patients withinflammatory bowel disease (IBD) and is thought to play a role in thedisease pathogenesis. Activated complement products were found at theluminal face of surface epithelial cells, as well as in the muscularismucosa and submucosal blood vessels in IBD patients (Woodruff, T. M., etal., Joflmmunol., 2003, 171: 5514-5520).

C5aR expression is upregulated on reactive astrocytes, microglia, andendothelial cells in an inflamed human central nervous system (Gasque,P. et al., Am. J. Pathol. 150: 31-41 (1997)). C5a might be involved inneurodegenerative diseases, such as Alzheimer disease (Mukherjee, P. etal., J. Neuroimmunol. 105: 124-130 (2000); O'Barr, S. et al., J.Neuroimmunol. (2000) 105: 87-94; Farkas, I., et al. J Immunol. (2003)170:5764-5771), Parkinson's disease, Pick disease and transmissiblespongiform encephalopathies. Activation of neuronal C5aR may induceapoptosis (Farkas I et al. J. Physiol. 1998; 507: 679-687). Therefore,inhibition of C5a and/or C5aR could also be useful in treatingneurodegenerative diseases.

There is some evidence that C5a production worsens inflammationassociated with atopic dermatitis (Neuber, K., et al., Immunology73:83-87, (1991)), and chronic urticaria (Kaplan, A. P., J Allergy Clin.Immunol. 114; 465-474, (2004).

Psoriasis is now known to be a T cell-mediated disease (Gottlieb, E. L.et al., Nat. Med. 1: 442-447 (1995)). However, neutrophils and mastcells may also be involved in the pathogenesis of the disease (Terui, T.et al., Exp. Dermatol. 9: 1-10; 2000); Werfel, T. et al., Arch.Dermatol. Res. 289: 83-86 (1997)). Neutrophil accumulation under thestratum corneum is observed in the highly inflamed areas of psoriaticplaques, and psoriatic lesion (scale) extracts contain highly elevatedlevels of C5a and exhibit potent chemotactic activity towardsneutrophils, an effect that can be inhibited by addition of a C5aantibody. T cells and neutrophils are chemo-attracted by C5a (Nataf, S.et al., J. Immunol. 162: 4018-4023 (1999); Tsuji, R. F. et al., JImmunol. 165: 1588-1598 (2000); Cavaillon, J. M. et al., Eur. J Immunol.20: 253-257 (1990)). Additionally expression of C5aR has beendemonstrated in plasmacytoid dendritic cells (pDC) isolated from lesionsof cutaneous lupus erythematous and these cells were shown to displaychemotactic behavior towards C5a, suggesting that blockade of C5aR onpDC might be efficacious in reducing pDC infiltration into inflamed skinin both SLE and psoriasis. Therefore C5a could be an importanttherapeutic target for treatment of psoriasis.

Immunoglobulin G-containing immune complexes (IC) contribute to thepathophysiology in a number of autoimmune diseases, such as systemiclupus erthyematosus, rheumatoid arthritis, Sjogren's disease,Goodpasture's syndrome, and hypersensitivity pneumonitis (Madaio, M. P.,Semin. Nephrol. 19: 48-56 (1999); Korganow, A. S. et al., Immunity 10:451-459 (1999); Bolten, W. K., Kidney Int. 50: 1754-1760 (1996); Ando,M. et al., Curr. Opin. Pulm. Med. 3: 391-399 (1997)). These diseases arehighly heterogeneous and generally affect one or more of the followingorgans: skin, blood vessels, joints, kidneys, heart, lungs, nervoussystem and liver (including cirrhosis and liver fibrosis). The classicalanimal model for the inflammatory response in these IC diseases is theArthus reaction, which features the infiltration of polymorphonuclearcells, hemorrhage, and plasma exudation (Arthus, M., C.R. Soc. Biol. 55:817-824 (1903)). Recent studies show that C5aR deficient mice areprotected from tissue injury induced by IC (Kohl, J. et al., Mot.Immunol. 36: 893-903 (1999); Baumann, U. et al., J. Immunol. 164:1065-1070 (2000)). The results are consistent with the observation thata small peptidic anti-C5aR antagonist inhibits the inflammatory responsecaused by IC deposition (Strachan, A. J. et al., J Immunol. 164:6560-6565 (2000)). Together with its receptor, C5a plays an importantrole in the pathogenesis of IC diseases. Inhibitors of C5a and C5aRcould be useful to treat these diseases.

DESCRIPTION OF RELATED ART

Non-peptide based C5a receptor antagonist have been reported as beingeffective for treating endotoxic shock in rats (Stracham, A. J., et al.,J. of Immunol. (2000), 164(12): 6560-6565); and for treating IBD in arat model (Woodruff, T. M., et al., J of Immunol., 2003, 171:5514-5520). Non-peptide based C5a receptor modulators also have beendescribed in the patent literature by Neurogen Corporation, (e.g.,WO2004/043925, WO2004/018460, WO2005/007087, WO03/082826, WO03/08828,WO02/49993, WO03/084524); Dompe S. P. A. (WO02/029187); The Universityof Queenland (WO2004/100975); and ChemoCentryx (WO2010/075257).

There is considerable experimental evidence in the literature thatimplicates increased levels of C5a with a number of diseases anddisorders, in particular in autoimmune and inflammatory diseases anddisorders. Thus, there remains a need in the art for new small organicmolecule modulators, e.g., agonists, preferably antagonists, partialagonists, of the C5a receptor (C5aR) that are useful for inhibitingpathogenic events, e.g., chemotaxis, associated with increased levelsanaphylatoxin activity. The present invention fulfills this and otherneeds.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provide compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein,ring vertex A⁰ is NH or C(O);each of ring vertices A¹ and A³ are independently selected from thegroup consisting of N, NH, CH, C(O) and C(R⁴);each of ring vertices A², A⁵ and A⁶ is independently selected from thegroup consisting of N, CH, and C(R⁴);ring vertex A⁴ is selected from the group consisting of N, N(C₁₋₄alkyl), CH, and C(R⁴); and no more than two of A³, A⁴, A⁵ and A⁶ are N;each of the dashed bonds independently is a single or double bond;R¹ is selected from the group consisting of heteroaryl, C₆₋₁₀ aryl,—C₁₋₈ alkylene-heteroaryl, —C₁₋₈alkylene-C₆₋₁₀ aryl, C₃₋₈ cycloalkyl,four to eight membered heterocycloalkyl, C₁₋₈ alkyl, C₁₋₈ haloalkyl,—C(O)NR^(1a)R^(1b), and —CO₂R^(1a); wherein the heterocycloalkyl groupis a 4 to 8 membered ring having from 1 to 3 heteroatoms as ringvertices selected from N, O and S; the heteroaryl group is a 5 to 10membered aromatic ring having from 1 to 3 heteroatoms as ring verticesselected from N, O and S;wherein R^(1a) and R^(1b) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, C₆₋₁₀ aryl, and —C₁₋₆ alkylene-C₆₋₁₀aryl;wherein R¹ is optionally substituted with 1 to 5 R⁵ substituents;R^(2a) and R^(2e) are each independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-S—C₁₋₆alkyl, CN, and halogen;R^(2b), R^(2c), and R^(2d) are each independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,—O—C₁₋₆ haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆alkyl-S—C₁₋₆ alkyl, cyano, and halogen;each R³ is independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl and hydroxyl, and optionally two R³ groups on thesame carbon atom are combined to form oxo (═O);each R⁴ is independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,—O—C₁₋₆ haloalkyl, halogen, cyano, hydroxyl, —S—C₁₋₆ alkyl, —C₁₋₆alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-S—C₁₋₆ alkyl, —NR^(4a)R^(4b),—CONR^(4a)R^(4b), —CO₂R^(4a), —COR^(4a), —OC(O)NR^(4a)R^(4b),—NR^(4a)C(O)R^(4b), —NR^(4a)C(O)₂R^(4b), and —NR^(4a)—C(O)NR^(4a)R^(4b);each R^(4a) and R^(4b) is independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;each R⁵ is independently selected from the group consisting of C₁₋₈alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₁₋₈ hydroxyalkyl,—C₁₋₈ alkyl-heterocycloalkyl, —C₁₋₈ alkyl-C₃₋₈ cycloalkyl, C₃₋₆cycloalkyl, heterocycloalkyl, halogen, OH, C₂₋₈ alkenyl, C₂₋₈ alkynyl,CN, C(O)R^(5a), —NR^(5b)C(O)R^(5a), —CONR^(5a)R^(5b), —NR^(5a)R^(5b),—C₁₋₈ alkylene-NR^(5a)R^(5b), —S—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl,—C₁₋₆ alkyl-S—C₁₋₆ alkyl, —OC(O)NR^(5a)R^(5b), —NR^(5a)C(O)₂R^(5b),—NR^(5a)—C(O)NR^(5b)R^(5b) and CO₂R^(5a); wherein the heterocycloalkylgroup is a 4 to 8 membered ring having from 1 to 3 heteroatoms as ringvertices selected from N, O and S;wherein each R^(5a) and R^(5b) is independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl, or when attachedto the same nitrogen atom R^(5a) and R^(5b) are combined with thenitrogen atom to form a five or six-membered ring having from 0 to 1additional heteroatoms as ring vertices selected from N, O, or S; andthe subscript n is 0, 1, 2 or 3.

In addition to the compounds provided herein, the present inventionfurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods for the use of these compounds intherapeutic methods, primarily to treat diseases associated C5asignaling activity.

In yet another aspect, the present invention provides methods ofdiagnosing disease in an individual. In these methods, the compoundsprovided herein are administered in labeled form to a subject, followedby diagnostic imaging to determine the presence or absence of C5aRand/or the localization of cells expressing a C5aR receptor. In arelated aspect, a method of diagnosing disease is carried out bycontacting a tissue or blood sample with a labeled compound as providedherein and determining the presence, absence, amount, or localization ofC5aR in the sample.

BRIEF DESCRIPTION OF THE DRAWINGS

NOT APPLICABLE

DETAILED DESCRIPTION OF THE INVENTION Abbreviation and Definitions

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁₋₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of such unsaturated alkyl groups includevinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), isobutenyl,2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “cycloalkyl”refers to hydrocarbon rings having the indicated number of ring atoms(e.g., C₃₋₆cycloalkyl) and being fully saturated or having no more thanone double bond between ring vertices. “Cycloalkyl” is also meant torefer to bicyclic and polycyclic hydrocarbon rings such as, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The term“heterocycloalkyl” refers to a cycloalkyl group that contain from one tofive heteroatoms selected from N, O, and S, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. The heterocycloalkyl may be a monocyclic, abicyclic or a polycylic ring system. Non limiting examples ofheterocycloalkyl groups include pyrrolidine, imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin,dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide,piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,tetrahydrofuran, tetrhydrothiophene, quinuclidine, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingfour or fewer carbon atoms. Similarly, “alkenylene” and “alkynylene”refer to the unsaturated forms of “alkylene” having double or triplebonds, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, and wherein the nitrogenand sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N and S may beplaced at any interior position of the heteroalkyl group. The heteroatomSi may be placed at any position of the heteroalkyl group, including theposition at which the alkyl group is attached to the remainder of themolecule. Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the terms“heteroalkenyl” and “heteroalkynyl” by itself or in combination withanother term, means, unless otherwise stated, an alkenyl group oralkynyl group, respectively, that contains the stated number of carbonsand having from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N and S may be placed at any interiorposition of the heteroalkyl group.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C═C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like).

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The term “hydroxyalkyl” is used in its conventional sense, and refers tobranched or straight chain alkyl group substituted with at least onehydroxyl group. The hydroxyl group may be at any position in the alkylgroup. For example, the term “C₁₋₄hydroxylalkyl” is meant to includehydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and thelike.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. Non-limitingexamples of aryl groups include phenyl, naphthyl and biphenyl, whilenon-limiting examples of heteroaryl groups include pyridyl, pyridazinyl,pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl,benzimidazolyl, benzopyrazolyl, benzooxazolyl, benzotriazolyl,benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl,thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for eachof the above noted aryl and heteroaryl ring systems are selected fromthe group of acceptable substituents described below.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. The compounds of the present invention may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

As used herein, a wavy line, “

”, that intersects a single, double or triple bond in any chemicalstructure depicted herein, represent the point attachment of the single,double, or triple bond to the remainder of the molecule.

DESCRIPTION OF THE EMBODIMENTS Compounds

In one aspect, the present invention provides compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein,ring vertex A⁰ is NH or C(O);each of ring vertices A¹ and A³ are independently selected from thegroup consisting of N, NH, CH, C(O) and C(R⁴);each of ring vertices A², A⁵ and A⁶ is independently selected from thegroup consisting of N, CH, and C(R⁴);ring vertex A⁴ is selected from the group consisting of N, N(C₁₋₄alkyl), CH, and C(R⁴);and no more than two of A³, A⁴, A⁵ and A⁶ are N;each of the dashed bonds independently is a single or double bond;R¹ is selected from the group consisting of heteroaryl, C₆₋₁₀ aryl,—C₁₋₈ alkylene-heteroaryl, —C₁₋₈alkylene-C₆₋₁₀ aryl, C₃₋₈ cycloalkyl,four to eight membered heterocycloalkyl, C₁₋₈ alkyl, C₁₋₈ haloalkyl,—C(O)NR^(1a)R^(1b), and —CO₂R^(1a); wherein the heterocycloalkyl groupis a 4 to 8 membered ring having from 1 to 3 heteroatoms as ringvertices selected from N, O and S; the heteroaryl group is a 5 to 10membered aromatic ring having from 1 to 3 heteroatoms as ring verticesselected from N, O and S;wherein R^(1a) and R^(1b) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, C₆₋₁₀ aryl, and —C₁₋₆ alkylene-C₆₋₁₀aryl;wherein R¹ is optionally substituted with 1 to 5 R⁵ substituents;R^(2a) and R^(2e) are each independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-S—C₁₋₆alkyl, CN, and halogen;R^(2b), R^(2c), and R^(2d) are each independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,—O—C₁₋₆ haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆alkyl-S—C₁₋₆ alkyl, cyano, and halogen;each R³ is independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl and hydroxyl, and optionally two R³ groups on thesame carbon atom are combined to form oxo (═O);each R⁴ is independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,—O—C₁₋₆ haloalkyl, halogen, cyano, hydroxyl, —S—C₁₋₆ alkyl, —C₁₋₆alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-S—C₁₋₆ alkyl, —NR^(4a)R^(4b),—CONR^(4a)R^(4b), —CO₂R^(4a), —COR^(4a), —OC(O)NR^(4a)R^(4b),—NR^(4a)C(O)R^(4b), —NR^(4a)C(O)₂R^(4b), and —NR^(4a)—C(O)NR^(4a)R^(4b);each R^(4a) and R^(4b) is independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;each R⁵ is independently selected from the group consisting of C₁₋₈alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₁₋₈ hydroxyalkyl,—C₁₋₈ alkyl-heterocycloalkyl, —C₁₋₈ alkyl-C₃₋₈ cycloalkyl, C₃₋₆cycloalkyl, heterocycloalkyl, halogen, OH, C₂₋₈ alkenyl, C₂₋₈ alkynyl,CN, C(O)R^(5a), —NR^(5b)C(O)R^(5a), —CONR^(5a)R^(5b), —NR^(5a)R^(5b),—C₁₋₈ alkylene-NR^(5a)R^(5b), —S—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl,—C₁₋₆ alkyl-S—C₁₋₆ alkyl, —OC(O)NR^(5a)R^(5b), —NR^(a)C(O)₂R^(5b),—NR^(5a)—C(O)NR^(5b)R^(5b) and —CO₂R^(5a); wherein the heterocycloalkylgroup is a 4 to 8 membered ring having from 1 to 3 heteroatoms as ringvertices selected from N, O and S;wherein each R^(5a) and R^(5b) is independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl, or when attachedto the same nitrogen atom R^(5a) and R^(5b) are combined with thenitrogen atom to form a five or six-membered ring having from 0 to 1additional heteroatoms as ring vertices selected from N, O, or S; andthe subscript n is 0, 1, 2 or 3.

Focusing on the ring portion having A⁰, A¹, A², A³, A⁴, A⁵, and A⁶, insome embodiments, the ring portion having A⁰, A¹, A², A³, A⁴, A⁵, and A⁶as ring vertices is a bicyclic heteroaryl selected from

wherein m is 0, 1, 2 or 3; and wherein the R⁴ substituents may beattached to any suitable carbon ring vertex of the bicyclic heteroaryl.

In some embodiments, the ring portion having A⁰, A¹, A², A³, A⁴, A⁵, andA⁶ as ring vertices is a bicyclic heteroaryl selected from

wherein m is 0, 1, 2, or 3.

In some embodiments, the each R⁴ is independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₄haloalkyl, halogen, cyano, hydroxyl, —NH₂, —CONR^(4a)R^(4b), and—CO₂R^(4a); wherein R^(4a) and R^(4b) are as defined above, and whereinthe R⁴ substituents may be attached to any suitable carbon ring vertexof the bicyclic heteroaryl.

A person of skill in the art will recognize that particular carbon atomsof the ring portion having A⁰, A¹, A², A³, A⁴, A⁵, and A⁶ cannot besubstituted with R⁴. For example, the carbon atom linking the bicyclicheteroaryl moiety (i.e. the ring portion having A⁰, A¹, A², A³, A⁴, A⁵,and A⁶) to the remainder of the molecule and the carbon atoms that aremembers of both ring systems in the fused bicyclic heteroaryl moiety(i.e. the two carbon atoms that are ring vertices in both the benzeneand five-membered ring system) cannot be substituted with R⁴ because anadditional substituent will exceed the valence of these carbon atoms.

In some embodiments, the ring portion having A⁰, A¹, A², A³, A⁴, A⁵, andA⁶ as ring vertices is a bicyclic heteroaryl selected from

Turning to R¹ and optional substituent(s), in some embodiments, R¹ isheteroaryl, C₆₋₁₀ aryl, —C₁₋₆ alkylene-heteroaryl, —C₁₋₆ alkylene-C₆₋₁₀aryl, four to eight membered heterocycloalkyl, C₃₋₈ cycloalkyl, C₁₋₈alkyl, —C(O)NR^(1a)R^(1b), and —CO₂R^(1a), wherein R^(1a) and R^(1b) andheterocycloalkyl are as defined above; the heteroaryl group is a 5 or 6membered aromatic ring having from 1 to 3 heteroatoms as ring verticesselected from N, O and S, and wherein R¹ is optionally substituted with1 to 3 R⁵ substituents.

In some embodiments, heterocycloalkyl groups of R¹ or R⁵ are from 4 to 6membered rings having from 1 to 3 heteroatoms as ring vertices selectedfrom N, O, and S. In some embodiments, the heteroaryl groups of R¹ or R⁵are 5 to 6 membered aromatic rings having from 1 to 3 heteroatoms asring vertices selected from N, O, and S. In some embodiments, the C₆₋₁₀aryl group of R¹ is phenyl.

In some embodiments, R¹ is pyridyl, pyrimidyl, pyrazinyl, thiadiazolyl,phenyl, benzyl, cyclopentyl, tetrahydropyranyl, —C(O)NR^(1a)R^(1b),—CO₂R^(1a), or C₁₋₈ alkyl, wherein R^(1a) and R^(1b) are as definedabove for Formula I, and wherein R¹ is optionally substituted with 1 to3 R⁵ substituents.

In some embodiments, R¹ is

each of which is optionally substituted with 1 to 3 R⁵ substituents.

In some embodiments, R¹ is

each of which is optionally substituted with 1 or 2 R⁵ substituents.

In some embodiments, R¹ is

In each of the described embodiments of R¹, R⁵ can be as defined aboveor as further defined as follows.

In some embodiments, each R⁵ is independently C₁₋₈ alkyl, C₁₋₈ alkoxy,C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₁₋₈ hydroxyalkyl, —C₁₋₈alkyl-heterocycloalkyl, C₃₋₆ cycloalkyl, halogen, —CONR^(5a)R^(5b),—NR^(5a)R^(5b), or —C₁₋₈ alkylene-NR^(5a)R^(5b), each R^(5a) and R^(5b)is independently selected from the group consisting of hydrogen and C₁₋₄alkyl, or when attached to the same nitrogen atom can be combined withthe nitrogen atom to form a 5 or 6-membered ring; and theheterocycloalkyl group is a 4 to 6 membered ring having from 1 to 3heteroatoms as ring vertices selected from N, O and S.

In some embodiments, R⁵ is halogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, —C(O)NR^(5a)R^(5b), and —CO₂R^(5a), wherein R^(5a) andR^(5b) are as defined above (with reference to Formula I).

In some embodiments, R⁵ is cyclopropyl, isopropyl, isopropyloxy, OMe,Me, Cl, F, —CONH₂, —CF₃, —O—CF₃,

In some embodiments, R¹ is

In some embodiments, R¹ is

Returning to Formula I and substituents R^(2a), R^(2b), R^(2c), R^(2d),and R^(2e), in some embodiments, R^(2a) and R^(2e) are eachindependently C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆haloalkyl, or halogen. In some embodiments, R^(2b), R^(2c), and R^(2d)are independently H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or halogen.

In some embodiments, R^(2b), R^(2c), and R^(2d) are each H.

In some embodiments, R^(2a) and R^(2e) are each independently Me, Et, F,Cl, OMe, OCF₃, and

In some embodiments, R^(2a) and R^(2e) are each independently C₁₋₆ alkylor C₁₋₆ haloalkyl.

In some embodiments, R^(2a) and R^(2e) are each independently methyl orethyl. In some embodiments, R^(2a) and R^(2e) are both methyl or areboth ethyl.

In some embodiments, the portion of Formula I represented by

Each R³ of Formula I, in some embodiments, is independently C₁₋₄ alkyl,or when two R³ groups are on the same carbon atom, they are combined toform oxo (═O).

In some embodiments, n, the subscript of R³, is 0. In some embodiments nis 2 and the two R³ groups are on the same carbon atom and are combinedto form oxo (═O).

In some embodiments, the portion of Formula (I) represented by

In some embodiments, the compound of Formula I is represented by Formula(Ia) or (Ib).

In embodiments where the compound of Formula (I) is represented byFormula (Ia), R¹, R³, n, R^(2a), R^(2e), and the ring portion having A¹,A², A³, A⁴, A⁵, and A⁶ as ring vertices are as defined above for Formula(I).

In embodiments where the compound of Formula (I) is represented byFormula (Ib), R¹, R^(2a), R^(2e), and the ring portion having A¹, A²,A³, A⁴, A⁵, and A⁶ as ring vertices are as defined above for Formula(I).

In some embodiments, the compound of Formula (I) is represented byFormula (Ic), (Id), or (Ie)

In embodiments where the compound of Formula (I) is represented byFormula (Ic), (Id) or (Ie), R¹, R⁴, m, R^(2a), and R^(2e) are as definedabove for Formula (I).

In some embodiments, the compound of Formula (I) is represented byFormula (If), (Ig), (Ih), or (Ii)

In embodiments where the compound of Formula (I) is represented byFormula (If), (Ig), (Ih), or (Ii), the ring portion having A¹, A², A³,A⁴, A⁵, and A⁶ as ring vertices, R^(2a), R^(2e), and R⁵ are as definedabove for Formula (I), and p is 0, 1 or 2.

In some embodiments, the compound of Formula (I) is represented byFormula (Ik), (Il), or (Im)

In embodiments where the compound of Formula (I) is represented byFormula (Ik), (Il) or (Im), R⁴, m, and R⁵ are as defined above forFormula (I), and p is 0, 1, or 2.

In some embodiments of Formulas (Ik), (Il), and (Im),

p is 1 or 2;m is 1 or 2;each R⁵ is independently C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₁₋₈haloalkoxy, C₁₋₈ hydroxyalkyl, —C₁₋₈ alkyl-heterocycloalkyl, C₃₋₆cycloalkyl, halogen, —CONR^(5a)R^(5b), —NR^(5a)R^(5b), and —C₁₋₈alkylene-NR^(5a)R^(5b), wherein each R^(5a) and R^(5b) is independentlyselected from the group consisting of hydrogen and C₁₋₄ alkyl, or whenattached to the same nitrogen atom can be combined with the nitrogenatom to form a 5 or 6-membered ring, wherein the heterocycloalkyl groupis a 4 to 6 membered ring having from 1 to 3 heteroatoms as ringvertices selected from N, O, and S; andeach R⁴ is independently C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₆ hydroxyalkyl,C₁₋₄ haloalkyl, halogen, cyano, hydroxyl, —NH₂, —CONR^(4a)R^(4b) and—CO₂R^(4a), wherein R^(4a) and R^(4b) are as defined above.

In some embodiments, the compound of Formula (I) is a compound describedin the Examples section.

Preparation of Compounds

Certain compounds of the invention can be prepared following methodologyas described in the Examples section of this document. In addition, thesyntheses of certain intermediate compounds that are useful in thepreparation of compounds of the invention are also described.

Pharmaceutical Compositions

In addition to the compounds provided above, compositions for modulatingC5a activity in humans and animals will typically contain apharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self emulsifications as described in U.S. PatentApplication 2002-0012680, hard or soft capsules, syrups, elixirs,solutions, buccal patch, oral gel, chewing gum, chewable tablets,effervescent powder and effervescent tablets. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, antioxidants andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated,enterically or otherwise, by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate may beemployed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to formosmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present invention are employed. As used herein, topicalapplication is also meant to include the use of mouth washes andgargles.

The compounds of this invention may also be coupled a carrier that is asuitable polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theinvention may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like. In one embodiment ofthe invention, the compound of the invention is coupled to a polymer orsemipermeable polymer matrix that is formed as a stent or stent-graftdevice.

The pharmaceutical compositions of the present disclosure may beformulated with one or more additional therapeutic agents. The one ormore additional therapeutic agents can include corticosteroids,steroids, immunosuppressants, or CD 20 inhibitors. In some embodiments,the one or more additional therapeutic agents include obinutuzumab,rituximab, ocrelizumab, cyclophosphamide, prednisone, hydrocortisone,hydrocortisone acetate, cortisone acetate, tixocortol pivalate,prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolonealcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide,fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodiumphosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone,hydrocortisone-17-valerate, halometasone, alclometasone dipropionate,beclomethasone, betamethasone valerate, betamethasone dipropionate,prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate,fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate,hydrocortisone-17-butyrate, hydrocortisone-17-aceponate,hydrocortisone-17-buteprate, ciclesonide and prednicarbate. Furtherdiscussions of combination therapy are included in the “Methods of Use”section of this application.

Methods of Use

The compounds of the invention may be used as agonists, (preferably)antagonists, partial agonists, inverse agonists, of C5a receptors in avariety of contexts, both in vitro and in vivo. In one embodiment, thecompounds of the invention are C5aR antagonist that can be used toinhibit the binding of C5a receptor ligand (e.g., C5a) to C5a receptorin vitro or in vivo. In general, such methods comprise the step ofcontacting a C5a receptor with a sufficient amount of one or more C5areceptor modulators as provided herein, in the presence of C5a receptorligand in aqueous solution and under conditions otherwise suitable forbinding of the ligand to C5a receptor. The C5a receptor may be presentin suspension (e.g., in an isolated membrane or cell preparation), in acultured or isolated cell, or in a tissue or organ.

Preferably, the amount of C5a receptor modulator contacted with thereceptor should be sufficient to inhibit C5a binding to C5a receptor invitro as measured, for example, using a radioligand binding assay,calcium mobilization assay, or chemotaxis assay as described herein.

In one embodiment of the invention, the C5a modulators of the inventionare used to modulate, preferably inhibit, the signal-transducingactivity of a C5a receptor, for example, by contacting one or morecompound(s) of the invention with a C5a receptor (either in vitro or invivo) under conditions suitable for binding of the modulator(s) to thereceptor. The receptor may be present in solution or suspension, in acultured or isolated cell preparation or within a patient. Anymodulation of the signal transducing activity may be assessed bydetecting an effect on calcium ion calcium mobilization or by detectingan effect on C5a receptor-mediated cellular chemotaxis. In general, aneffective amount of C5a modulator(s) is an amount sufficient to modulateC5a receptor signal transducing activity in vitro within a calciummobilization assay or C5a receptor-mediated cellular chemotaxis within amigration assay.

When compounds of the invention are used to inhibit C5areceptor-mediated cellular chemotaxis, preferably leukocyte (e.g.,neutrophil) chemotaxis, in an in vitro chemotaxis assay, such methodscomprise contacting white blood cells (particularly primate white bloodcells, especially human white blood cells) with one or more compounds ofthe invention. Preferably the concentration is sufficient to inhibitchemotaxis of white blood cells in an in vitro chemotaxis assay, so thatthe levels of chemotaxis observed in a control assay are significantlyhigher, as described above, than the levels observed in an assay towhich a compound of the invention has been added.

In another embodiment, the compounds of the present invention furthercan be used for treating patients suffering from conditions that areresponsive to C5a receptor modulation. As used herein, the term“treating” or “treatment” encompasses both disease-modifying treatmentand symptomatic treatment, either of which may be prophylactic (i.e.,before the onset of symptoms, in order to prevent, delay or reduce theseverity of symptoms) or therapeutic (i.e., after the onset of symptoms,in order to reduce the severity and/or duration of symptoms). As usedherein, a condition is considered “responsive to C5a receptormodulation” if modulation of C5a receptor activity results in thereduction of inappropriate activity of a C5a receptor. As used herein,the term “patients” include primates (especially humans), domesticatedcompanion animals (such as dogs, cats, horses, and the like) andlivestock (such as cattle, pigs, sheep, and the like), with dosages asdescribed herein.

Conditions that can be Treated by C5a Modulation:

Autoimmune disorders—e.g., Rheumatoid arthritis, systemic lupuserythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis,lupus glomerulonephritis, psoriasis, Crohn's disease, vasculitis,irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchialasthma, dense deposit disease, pemphigus, pemphigoid, scleroderma,myasthenia gravis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome (and associated glomerulonephritis and pulmonaryhemorrhage), C3-glomerulopathy, C3-glomerulonephritis,membranoproliferative glomerulonephritis, Kawasaki disease, IGsnephropathy, immunovasculitis, tissue graft rejection, graft versus hostdisease, hyperacute rejection of transplanted organs; and the like.

Inflammatory disorders and related conditions—e.g., Neutropenia, sepsis,septic shock, Alzheimer's disease, multiple sclerosis, neutrophilia,stroke, inflammatory bowel disease (IBD), inflammation associated withsevere burns, lung injury, and ischemia-reperfusion injury,osteoarthritis, as well as acute (adult) respiratory distress syndrome(ARDS), chronic pulmonary obstructive disorder (COPD), systemicinflammatory response syndrome (SIRS), atopic dermatitis, psoriasis,chronic urticaria and multiple organ dysfunction syndrome (MODS)Hemolytic uremic syndrome, atypical hemolytic uremic syndrome (aHUS).Also included are pathologic sequellae associated with insulin-dependentdiabetes mellitus (including diabetic retinopathy), lupus nephropathy,Heyman nephritis, membranous nephritis and other forms ofglomerulonephritis, contact sensitivity responses, and inflammationresulting from contact of blood with artificial surfaces that can causecomplement activation, as occurs, for example, during extracorporealcirculation of blood (e.g., during hemodialysis or via a heart-lungmachine, for example, in association with vascular surgery such ascoronary artery bypass grafting or heart valve replacement), or inassociation with contact with other artificial vessel or containersurfaces (e.g., ventricular assist devices, artificial heart machines,transfusion tubing, blood storage bags, plasmapheresis,plateletpheresis, and the like). Also included are diseases related toischemia/reperfusion injury, such as those resulting from transplants,including solid organ transplant, and syndromes such as ischemicreperfusion injury, ischemic colitis and cardiac ischemia. Compounds ofthe instant invention may also be useful in the treatment of age-relatedmacular degeneration (Hageman et al, P.N.A.S. 102: 7227-7232, 2005).

Cardiovascular and Cerebrovascular Disorders—e.g., myocardialinfarction, coronary thrombosis, vascular occlusion, post-surgicalvascular reocclusion, atherosclerosis, traumatic central nervous systeminjury, and ischemic heart disease. In one embodiment, an effectiveamount of a compound of the invention may be administered to a patientat risk for myocardial infarction or thrombosis (i.e., a patient who hasone or more recognized risk factor for myocardial infarction orthrombosis, such as, but not limited to, obesity, smoking, high bloodpressure, hypercholesterolemia, previous or genetic history ofmyocardial infarction or thrombosis) in order reduce the risk ofmyocardial infarction or thrombosis.

Oncologic Diseases or Disorders—e.g., melanoma, lung cancer, lymphoma,sarcoma, carcinoma, fibrosarcoma, liposarcoma, chondrosarcoma,osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma,mesothelioma, meningioma, leukemia, lymphoma, leiomyosarcoma,rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogeniccarcinoma, renal cell carcinoma, hepatocellular carcinoma, transitionalcell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilm'stumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma,cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma,lymphangioma, osteoma, chondroma, lipoma and fibroma.

Diseases of Vasculitis—Vasculitic dseases are characterized byinflammation of the vessels. Infliltration of leukocytes leads todestruction of the vessel walls, and the complement pathway is believedto play a major role in initiating leukocyte migration as well as theresultant damage manifested at the site of inflammation (Vasculitis,Second Edition, Edited by Ball and Bridges, Oxford University Press, pp47-53, 2008). The compounds provided in the present invention can beused to treat leukoclastic vasculitis, Anti-neutrophil cytoplasmicantibody (ANCA) associated vasculitis, immune vasculitis Wegener'sgranulomatosis, microscopic polyangiitis, Churg-Strauss syndrome,Henoch-Schonlein purpura, polyateritis nodosa, Rapidly ProgressiveGlomerulonephritis (RPGN), cryoglobulinaemia, giant cell arteritis(GCA), Behcet's disease and Takayasu's arteritis (TAK).

HIV infection and AIDS—C5a receptor modulators provided herein may beused to inhibit HIV infection, delay AIDS progression or decrease theseverity of symptoms or HIV infection and AIDS.

Neurodegenerative disorders and related diseases—Within further aspects,C5a antagonists provided herein may be used to treat Alzheimer'sdisease, multiple sclerosis, and cognitive function decline associatedwith cardiopulmonary bypass surgery and related procedures.

In one embodiment of the invention, the compounds of the invention canbe used for the treatment of diseases selected from the group consistingof sepsis (and associated disorders), COPD, rheumatoid arthritis, lupusnephritis and multiple sclerosis.

Treatment methods provided herein include, in general, administration toa patient an effective amount of one or more compounds provided herein.Suitable patients include those patients suffering from or susceptibleto (i.e., prophylactic treatment) a disorder or disease identifiedherein. Typical patients for treatment as described herein includemammals, particularly primates, especially humans. Other suitablepatients include domesticated companion animals such as a dog, cat,horse, and the like, or a livestock animal such as cattle, pig, sheepand the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound one or more compoundsprovided herein. In a preferred embodiment, the compound(s) of theinvention are preferably administered to a patient (e.g., a human)orally or topically. The effective amount may be an amount sufficient tomodulate C5a receptor activity and/or an amount sufficient to reduce oralleviate the symptoms presented by the patient. Preferably, the amountadministered is sufficient to yield a plasma concentration of thecompound (or its active metabolite, if the compound is a pro-drug) highenough to detectably inhibit white blood cell (e.g., neutrophil)chemotaxis in vitro. Treatment regimens may vary depending on thecompound used and the particular condition to be treated; for treatmentof most disorders, a frequency of administration of 4 times daily orless is preferred. In general, a dosage regimen of 2 times daily is morepreferred, with once a day dosing particularly preferred. It will beunderstood, however, that the specific dose level and treatment regimenfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination (i.e., other drugsbeing administered to the patient) and the severity of the particulardisease undergoing therapy, as well as the judgment of the prescribingmedical practitioner. In general, the use of the minimum dose sufficientto provide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using medical or veterinarycriteria suitable for the condition being treated or prevented.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving pathogenic C5a activity (about 0.5mg to about 7 g per human patient per day). The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.For compounds administered orally, transdermally, intravaneously, orsubcutaneously, it is preferred that sufficient amount of the compoundbe administered to achieve a serum concentration of 5 ng(nanograms)/mL-10 μg (micrograms)/mL serum, more preferably sufficientcompound to achieve a serum concentration of 20 ng-1 μg/ml serum shouldbe administered, most preferably sufficient compound to achieve a serumconcentration of 50 ng/ml-200 ng/ml serum should be administered. Fordirect injection into the synovium (for the treatment of arthritis)sufficient compounds should be administered to achieve a localconcentration of approximately 1 micromolar.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily, three times daily, or less ispreferred, with a dosage regimen of once daily or 2 times daily beingparticularly preferred. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, and rate of excretion, drugcombination (i.e., other drugs being administered to the patient), theseverity of the particular disease undergoing therapy, and otherfactors, including the judgment of the prescribing medical practitioner.

Combination Therapy

The presently disclosed compounds may be used in combination with one ormore additional therapeutic agents that are used in the treatment,prevention, suppression or amelioration of the diseases or conditionsfor which compounds and compositions of the present invention areuseful. Such one or more additional therapeutic agents may beadministered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound or composition of thepresent invention. When a compound or composition of the presentinvention is used contemporaneously with one or more other drugs, apharmaceutical composition containing such other drugs in addition tothe compound or composition of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients ortherapeutic agents, in addition to a compound or composition of thepresent invention.

Examples of the one or more additional therapeutic agents that may becombined with a compound or composition of the present invention, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to: (a) VLA-4 antagonists, (b) steroids andcorticosteroids, such as beclomethasone, betamethasone (includingbetamethasone sodium phosphate, betamethasone valerate, betamethasonedipropionate) prednisone, prenisolone, methylprednisolone, mometasone,dexamethasone (including dexamethasone sodium phosphate), fluticasone,cortisone (including cortisone acetate) hydrocortisone (includinghydrocortisone acetate, hydrocortisone-17-valerate,hydrocortisone-17-butyrate, hydrocortisone-17-aceponate,hydrocortisone-17-buteprate), budesonide, desonide, fluocinonide(including fluocinolone acetonide), triamcinolone (includingtriamcinolone acetonide and triamcinolone alcohol), tixocortol(including tixocortol pivalate) fluocortolone (including fluocortolonecaproate and fluocortolone pivalate), amcinonide, halcinonide,halometasone, fluprednidene acetate, salmeterol, salmeterol, salbutamol,ciclesonide, formeterol, alclometasone (including alclometasonedipropionate), prednicarbate, clobetasone (includingclobetasone-17-butrate), clobetasol (includingclobetasol-17-propionate); (c) immunosuppressants such as cyclosporine(cyclosporine A, Sandimmune®, Neoral®), tacrolirnus (FK-506, Prograf®),rapamycin (sirolimus, Rapamune®) and other FK-506 typeimmunosuppressants, and rnycophenolate, e.g., mycophenolate mofetil(CellCept8); (d) antihistamines (H1-histamine antagonists) such asbromopheniramine, chlorpheniramine, dexchloipheniramine, triprolidine,clemastine, diphenhydramine, diphenylpyraline, tripelennamine,hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine,cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non steroidal antiasthmatics (e.g., terbutaline, metaproterenol, fenoterol, isoetharine,albuterol, bitolterol and pirbuterol), theophylline, cromolyn sodium,atropine, ipratropium bromide, leukotriene antagonists (e.g.,zafmlukast, montelukast, pranlukast, iralukast, pobilukast andSKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005);(f) non steroidal anti-inflammatory agents (NSAIDs) such as propionicacid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid,carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen,indoprofen, ketoprofen, rniroprofen, naproxen, oxaprozin, pirprofen,pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acidderivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin andzomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetyl salicylic acid and sulfasalazine) and thepyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone); (g) cyclooxygenase-2 (COX-2)inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h)inhibitors of phosphodiesterase type IV (PDE IV); (i) gold compoundssuch as auranofin and aurothioglucose, (j) etanercept (Enbre10), (k)cyclophosphamide, (1) antibody therapies such as orthoclone (OKT3),daclizumab (Zenapax®), basiliximab (Simulect®) and infliximab(Remicade®), (m) antibody therapies targeting CD20 such as obinutuzumab,rituximab, or ocrelizumab; (n) chemotherapeutic agents suchanthracyclines (e.g., daunorubicin (daunomycin; rubidomycin),doxorubicin, epirubicin, idarubicin, and valrubicin), mitoxantrone, andpixantrone; platinum-based agents (e.g., cisplatin, carboplatin,oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, andlipoplatin); tamoxifen and metabolites thereof such as4-hydroxytamoxifen (afimoxifene) and N-desmethyl-4-hydroxytamoxifen(endoxifen); taxanes such as paclitaxel (taxol) and docetaxel;alkylating agents (e.g., nitrogen mustards such as mechlorethamine(HN2), cyclophosphamide, ifosfamide, melphalan (L-sarcolysin), andchlorambucil); ethylenimines and methylmelamines (e.g.,hexamethylmelamine, thiotepa, alkyl sulphonates such as busulfan,nitrosoureas such as carmustine (BCNU), lomustine (CCNLJ), semustine(methyl-CCN-U), and streptozoein (streptozotocin), and triazenes such asdecarbazine (DTIC; dimethyltriazenoimidazolecarboxamide));antimetabolites (e.g., folic acid analogues such as methotrexate(amethopterin), pyrimidine analogues such as fluorouracil(5-fluorouracil; 5-FU), floxuridine (fluorodeoxyuridine; FUdR), andcytarabine (cytosine arabinoside), and purine analogues and relatedinhibitors such as mercaptopurine (6-mercaptopurine; 6-MP), thioguanine(6-thioguanine; 6-TG), and pentostatin (2′-deoxycofonnycin)); (o) otherantagonists of the chemokine receptors, especially CXCR2, CXCR3, CCR2,CCR3, CCR4, CCR7, CX3CR1 and CXCR6.

The disease or disorder being treated will determine which additionaltherapeutic agent or therapeutic agents are most appropriatelyadministered in combination with the compounds of the presentinvention—such determination can be made by a person of skill in theart.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of the compound of the present inventionto the NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

Non-Pharmaceutical Applications

In another aspect of the invention, the compounds of the invention canbe used in a variety of non-pharmaceutical in vitro and in vivoapplication. For example, the compounds of the invention may be labeledand used as probes for the detection and localization of C5a receptor(cell preparations or tissue sections samples). The compounds of theinvention may also be used as positive controls in assays for C5areceptor activity, i.e., as standards for determining the ability of acandidate agent to bind to C5a receptor, or as radiotracers for positronemission tomography (PET) imaging or for single photon emissioncomputerized tomography (SPECT). Such methods can be used tocharacterize C5a receptors in living subjects. For example, a C5areceptor modulator may be labeled using any of a variety of well knowntechniques (e.g., radiolabeled with a radionuclide such as tritium), andincubated with a sample for a suitable incubation time (e.g., determinedby first assaying a time course of binding). Following incubation,unbound compound is removed (e.g., by washing), and bound compounddetected using any method suitable for the label employed (e.g.,autoradiography or scintillation counting for radiolabeled compounds;spectroscopic methods may be used to detect luminescent groups andfluorescent groups). As a control, a matched sample containing labeledcompound and a greater (e.g., 10-fold greater) amount of unlabeledcompound may be processed in the same manner. A greater amount ofdetectable label remaining in the test sample than in the controlindicates the presence of C5a receptor in the sample. Detection assays,including receptor autoradiography (receptor mapping) of C5a receptor incultured cells or tissue samples may be performed as described by Kuharin sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998)John Wiley & Sons, New York.

The compounds provided herein may also be used within a variety of wellknown cell separation methods. For example, modulators may be linked tothe interior surface of a tissue culture plate or other support, for useas affinity ligands for immobilizing and thereby isolating, C5areceptors (e.g., isolating receptor-expressing cells) in vitro. In onepreferred application, a modulator linked to a fluorescent marker, suchas fluorescein, is contacted with the cells, which are then analyzed (orisolated) by fluorescence activated cell sorting (FACS).

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR spectra wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare provided relative to TMS and are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet) and number of protons. Mass spectrometry results are reportedas the ratio of mass over charge, followed by the relative abundance ofeach ion (in parenthesis). In the examples, a single m/e value isreported for the M+H (or, as noted, M−H) ion containing the most commonatomic isotopes. Isotope patterns correspond to the expected formula inall cases. Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Hewlett-Packard MSD electrospray mass spectrometer usingthe HP1100 HPLC for sample delivery. Normally the analyte was dissolvedin methanol at 0.1 mg/mL and 1 microliter was infused with the deliverysolvent into the mass spectrometer, which scanned from 100 to 1500daltons. All compounds could be analyzed in the positive ESI mode, usingacetonitrile/water with 1% formic acid as the delivery solvent. Thecompounds provided below could also be analyzed in the negative ESImode, using 2 mM NH₄OAc in acetonitrile/water as delivery system.

The following abbreviations are used in the Examples and throughout thedescription of the invention:

EtOH: Ethanol

EtONa: Sodium ethoxide

THF: Tetrahydrofuran

TLC: Thin layer chromatography

MeOH: Methanol

Compounds within the scope of this invention can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisinvention, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Synthesis of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

Caution. Diazonium Formation could be Potentially Dangerous, PleaseHandle with Care and Wear Proper Personal Protection Equipment!

Step a: To a 250 mL flask charged with 90 mL of concentratedhydrochloric acid under magnetic stirring was added 2,6-diethylaniline(10 g, 67 mmol). The resulting mixture was stirred for 30 min and cooledwith an ice salt bath until the internal temperature reached −5° C. Asolution of sodium nitrite (5.5 g, 80 mmol) in water (60 mL) was addedslowly to the above mixture while maintaining the internal temperaturebelow 5° C.

Separately, tin(II) chloride dihydrate (31.6 g, 140 mmol) was added to a500 mL 3-neck round bottom flask charged with concentrated hydrochloricacid (60 mL) under mechanical stirring. The resulting solution was thencooled with an ice bath.

The diazonium slurry was then filtered into the 500 mL flask containingthe cooled tin chloride solution with vigorous stirring. After 90 min,the reaction mixture was transferred to a 500 mL Erlenmeyer flask andthe flask was rinsed with water (20 mL) and chloroform (8 mL). Thecombined mixture was stirred overnight at room temperature. The entireliquid layer was decanted to give a wet solid. The material thusrecovered was dried in vacuo for one day and then transferred to a 500mL 3-neck round bottom flask equipped with an overhead mechanicalstirrer and stirred with ether (180 mL). The resulting mixture wascooled in an ice bath, and NaOH solution (10 N, 30 mL) was added slowlyto the above mixture while maintaining the inner temperature below 12°C. After the addition, the mixture was allowed to stand for 2 h on ice.The ether layer was decanted into a 500 mL flask, and a stream ofhydrogen chloride gas was bubbled into the ether solution whilestirring. The resulting precipitate was collected by filtration toafford (2,6-diethylphenyl)hydrazine hydrochloride. MS: (ES) m/zcalculated for C₁₀H₁₇N₂ [M+H]⁺ 165.1, found 165.1.

Step b: N,N-diisopropylethylamine (8 mL, 46.0 mmol) was added to amixture of (2,6-diethylphenyl)hydrazine hydrochloride (8 g, 39.9 mmol),tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (5 g, 22.3 mmol) andEtOH (60 mL) in a 250 mL round bottom flask under magnetic stirring. Theresulting mixture was stirred under reflux for 3 h. Glacial acetic acid(12 mL, 208 mmol) was added and the mixture was stirred under reflux foranother 2 h. The solvent was removed under reduced pressure and theresidue was dissolved in EtOAc and washed with NaOH solution (2N),brine, and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by silica gel flash chromatography(5 to 55% EtOAc in hexanes) to give tert-butyl3-amino-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₁H₃₁N₄O₂ [M+H]⁺ 371.2, found 371.2.

Caution. Diazonium Formation could be Potentially Dangerous, PleaseHandle with Care and Wear Proper Personal Protection Equipment!

Isopentyl nitrite (4 mL, 28.6 mmol) was added slowly at room temperatureto a mixture of tert-butyl3-amino-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(3 g, 8.1 mmol), CuBr (4 g, 27.9 mmol) and MeCN (50 mL) in a 250 mLround bottom flask under magnetic stirring. The resulting mixture wasstirred at room temperature for 1 h, diluted with EtOAc, filteredthrough Celite, washed with saturated NH₄Cl solution, and dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (2 to 25% EtOAc inhexanes) to give tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₁H₂₉BrN₃O₂[M+H]⁺ 434.1, found 434.2.

Synthesis of7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

Step a: A solution of vinylmagenesium bromide in THE (1 M, 60 mL, 60mmol) was added rapidly to a solution of 4-bromo-1-chloro-2-nitrobenzene(4.7 g, 19.9 mmol) in anhydrous THF (50 mL) under N₂ and vigorouslystirring at −60° C. The reaction mixture was stirred at the sametemperature and allowed to warm to −30° C. over 1.5 h. The reaction wasquenched with saturated NH₄Cl solution and the mixture was allowed towarm up to room temperature over 1 h. The reaction mixture was dilutedwith EtOAc, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (2 to 20% EtOAc in hexanes) to give4-bromo-7-chloro-1H-indole. MS: (ES) m/z calculated for C₈H₆BrClN [M+H]⁺229.9, found 229.9.

Step b: To a suspension of 4-bromo-7-chloro-1H-indole (1.7 g, 7.4 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.4 g, 13.4mmol), and KOAc (3 g, 30.6 mmol) in p-dioxane (12 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (800 mg, 0.97 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for3 h. The reaction mixture was diluted with EtOAc, filtered throughCelite. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (5 to 20% EtOAc inhexanes) to give7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. MS:(ES) m/z calculated for C₁₅H₂₀BFNO₂ [M+H]⁺ 276.1, found 276.1.

Synthesis of 2,3-difluoro-5-(1-methylethyl)pyridine

To a suspension of 5-bromo-2,3-difluoropyridine (9.0 g, 46 mmol),4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (11 g, 65mmol), and sodium carbonate (15 g, 140 mmol) in a mixture of dioxane(150 mL) and water (40 mL) was added Pd(dppf)Cl₂ complex withdichloromethane (2.0 g, 2.4 mmol). The reaction mixture was degassed(N₂) for 2 min and refluxed for 1 h. Dioxane was removed in vacuo andthe residue was taken up in dichloromethane and water. The organic phasewas separated, filtered through Celite, and the solvent was removedunder reduced pressure. The residue was purified by silica gel flashchromatography (5% EtOAc in hexanes) to obtain2,3-difluoro-5-(1-methylethenyl)pyridine. ¹H NMR (400 MHz, CDCl₃) δ 8.04(t, J=1.9 Hz, 1H), 7.58-7.65 (m, 1H), 5.39 (s, 1H), 5.22 (s, 1H), 2.14(s, 3H).

To the above 2,3-difluoro-5-(1-methylethenyl)pyridine (5.9 g, 38 mmol)dissolved in EtOAc (100 mL) was added 10% Pd/C (Degussa type E101 NE/W,420 mg). The mixture was stirred under one atmosphere of hydrogen for 17h. When the reaction was complete, the mixture was filtered throughCelite and solvent was removed in vacuo to give2,3-difluoro-5-(1-methylethyl)pyridine. ¹H NMR (400 MHz, CDCl₃) δ 7.82(t, J=1.7 Hz, 1H), 7.38-7.45 (m, 1H), 2.91-3.10 (m, 1H), 1.27 (d, J=7.2Hz, 6H).

Synthesis of tert-butyl4-bromo-6-fluoro-7-(hydroxymethyl)-1H-benzo[d]imidazole-1-carboxylate

Step a: A mixture of methyl 4-bromo-2,6-difluorobenzoate (5.5 g, 21.9mmol), conc. H₂SO₄ (25 mL) and HNO₃ (25 mL) was stirred at roomtemperature for 0.5 hr. It was then poured onto ice and extracted withEtOAc. The organic layer was separated, dried over Na₂SO₄, concentratedon a rotary evaporator under reduced pressure and the residue waspurified by silica gel flash chromatograph (0 to 40% EtOAc/hexanes) togive methyl 4-bromo-2,6-difluoro-3-nitrobenzoate. MS: (ES) m/zcalculated for C₈H₄BrF₂NO₄ [M+H]⁺ 295.1, found 295.1.

Step b: A mixture of methyl 4-bromo-2,6-difluoro-3-nitrobenzoate (6.0 g,20.2 mmol) and NH₃/dioxane (0.5M, 200 mL, 100 mmol) was stirred at 60°C. for 1 hr. To the mixture was then added NH₃/MeOH (1.0M, 100 mL, 100mmol) and heating continued for another 15 min at the same temperature.It was then cooled to room temperature, poured into water and extractedwith EtOAc. The organic layer was separated, dried over Na₂SO₄,concentrated on a rotary evaporator under reduced pressure and theresidue was purified by silica gel flash chromatograph (0 to 100%EtOAc/hexanes) to give methyl 2-amino-4-bromo-6-fluoro-3-nitrobenzoate.MS: (ES) m/z calculated for C₈H₆BrFN₂O₄[M+H]⁺ 292.0, found 292.0.

Step c: A mixture of methyl 2-amino-4-bromo-6-fluoro-3-nitrobenzoate(3.6 g, 12.2 mmol), Fe (25 g, 447 mmol), NH₄Cl (30 g, 560 mmol),trimethyl orthoformate (50 mL), formic acid (70 mL) and IPA (120 mL)conc. H₂SO₄ (25 mL) and HNO₃ (25 mL) was stirred at 80° C. for 5 hours.It was then cooled to room temperature, diluted with 20% MeOH/DCM andfiltered through celite. The filtrate was collected, concentrated on arotary evaporator under reduced pressure and the residue was purified bysilica gel flash chromatograph (0 to 100% EtOAc/hexanes) to give methyl4-bromo-6-fluoro-1H-benzo[d]imidazole-7-carboxylate. MS: (ES) m/zcalculated for C₉H₆BrFN₂O₂[M+H]⁺ 272.2, found 272.2.

Step d: A mixture of methyl4-bromo-6-fluoro-1H-benzo[d]imidazole-7-carboxylate (0.64 g, 2.35 mmol)and LiAlH₄ (3.3 mL, 1M/ether, 3.3 mmol) in THF (7 mL) was stirred at 0°C. for 1 hr. It was then poured into aq. NH₄OH and extracted withIPA/CHCl₃. The organic layer was separated, dried over Na₂SO₄,concentrated on a rotary evaporator under reduced pressure. The residuewas purified by silica gel flash chromatograph (0 to 30% MeOH/EtOAc) togive (4-bromo-6-fluoro-1H-benzo[d]imidazol-7-yl)methanol. MS: (ES) m/zcalculated for C₈H₆BrFN₂O [M+H]⁺ 243.9, found 243.9.

A mixture of (4-bromo-6-fluoro-1H-benzo[d]imidazol-7-yl)methanol (0.48g, 1.96 mmol), (BOC)₂O (2.0 g, 9.2 mmol) and DMAP (0.36 g, 3 mmol) inDCM (25 mL) was stirred at room temperature for 1 hr. It was then pouredinto aq. NaHCO₃ and extracted with DCM. The organic layer was separated,dried over Na₂SO₄, concentrated on a rotary evaporator under reducedpressure. The residue was purified by silica gel flash chromatograph (0to 60% EtOAc/hexanes) to give tert-butyl4-bromo-6-fluoro-7-(hydroxymethyl)-1H-benzo[d]imidazole-1-carboxylate.MS: (ES) m/z calculated for C₁₃H₁₄BrFN₂O₃[M+H]⁺ 344.0, found 344.0.

Synthesis of tert-butyl4-bromo-7-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

Step a: To solution of 2-bromo-5-chloropyridine (25 g, 0.13 mol) in 70mL of TFA was added dropwise a 35% wt/wt aqueous solution of H₂O₂. Thesolution was heated at 70° C. for 16 hrs then quenched with a saturatedsolution of sodium sulfite. The mixture was extracted with ethyl acetateand the organic layers were combined, dried with sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (70% EtOAc in hexanes) to afford2-bromo-5-chloropyridine 1-oxide. MS: (ES) m/z calculated for C₅H₃BrClNO[M+H]⁺ 207.9, found 207.9.

Step b: To a solution of 2-bromo-5-chloropyridine 1-oxide in 100 mL ofH₂SO₄ at 0° C. was added dropwise 46 mL of HNO₃. The solution was heatedat 65° C. for 16 hrs then quenched with 250 mL of H₂O. The mixture wasstirred at room temperature overnight and the precipitate was filteredand collected. The solid was further purified on silica gel columnchromatography to yield 2-bromo-5-chloro-4-nitropyridine 1-oxide2-bromo-5-chloropyridine 1-oxide. MS: (ES) m/z calculated forC₅H₂BrClN₂O₃[M+H]⁺ 252.9, found 252.9.

Step c: To a solution of PBr₃ (1.32 mL, 14.3 mmol) in 3 mL of DCM wasadded portion-wise 2-bromo-5-chloro-4-nitropyridine 1-oxide2-bromo-5-chloropyridine 1-oxide (1.5 g, 6.0 mmol). The mixture wasstirred at room temperature for 30 min, then cooled to 0° C. andquenched slowly with ice water. The aqueous layer was extracted withethyl acetate and the combined organic layers was dried with sodiumsulfate, filtered and concentrated. The residue was purified by silicagel column chromatography (10% ethyl acetate in hexanes) to give2-bromo-5-chloro-4-nitropyridine.

Step d: To a solution of 2-bromo-5-chloro-4-nitropyridine (1.6 g, 6.6mmol) in 26 mL of THF at −78° C. was added dropwise a solution of 1.0 Mvinylmagnesium bromide in THF (23.2 mL, 23.2 mmol). The solution wasstirred at −78° C. for 30 min then quenched slowly with a solution of 1N HCl. The aqueous and organic layers were separated and the aqueouslayer was washed with ethyl acetate. The combined organic layers wasdried with sodium sulfate, filtered and concentrated. The residue waspurified by silica gel column chromatography (40% ethyl acetate inhexanes) to afford 4-bromo-7-chloro-1H-pyrrolo[3,2-c]pyridine. MS: (ES)m/z calculated for C₇H₄BrClN₂ [M+H]⁺ 230.9, found 230.9.

Step e: To a solution of 4-bromo-7-chloro-1H-pyrrolo[3,2-c]pyridine (0.3g, 1.3 mmol) in 2.6 mL of acetonitrile was added di-tert-butyldicarbonate (0.6 mL, 2.6 mmol) followed by DMAP (0.16 g, 1.3 mmol). Thesolution was stirred at room temperature for 15 min. The mixture wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (10% ethylacetate in hexanes) to provide tert-butyl4-bromo-7-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate. MS: (ES) m/zcalculated for C₁₂H₁₂BrClN₂O₂ [M+H]⁺ 331.0, found 331.0.

Example 1 Synthesis of3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: Iodomethane (1.5 mL, 24 mmol) was added to a suspension of4-bromo-2-chloro-6-nitrophenol (3.2 g, 12.7 mmol) and K₂CO₃ (3 g, 21.7mmol) in DMF (40 mL) in a 250 mL round bottom flask under magneticstirring. The resulting mixture was stirred at 45° C. for 4 h, dilutedwith EtOAc, washed with brine, and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (2 to 25% EtOAc in hexanes) to give5-bromo-1-chloro-2-methoxy-3-nitrobenzene. MS: (ES) m/z calculated forC₇H₆BrClNO₃ [M+H]⁺ 265.9, found 265.9.

A solution of vinylmagenesium bromide in THF (1 M, 40 mL, 40 mmol) wasadded rapidly to a solution of 5-bromo-1-chloro-2-methoxy-3-nitrobenzene(3.2 g, 12 mmol) in anhydrous THF (40 mL) under N₂ and vigorouslystirring at −60° C. The reaction mixture was allowed to warm to −30° C.over 1.5 h. The reaction was quenched with saturated NH₄Cl solution andthe mixture was allowed to warm up to room temperature over 1 h. Thereaction mixture was diluted with EtOAc, washed with brine and driedover MgSO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (2 to 20% EtOAcin hexanes) to give 4-bromo-6-chloro-7-methoxy-1H-indole. MS: (ES) m/zcalculated for C₉H₈BrClNO [M+H]⁺ 259.9, found 259.9.

Step b: To a suspension of 4-bromo-6-chloro-7-methoxy-1H-indole (1.2 g,4.6 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(2.4 g, 9.5 mmol), and KOAc (2.3 g, 23.4 mmol) in DMSO (10 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (600 mg, 0.73 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 120° C. for2 h. The reaction mixture was diluted with EtOAc, filtered throughCelite, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by silica gel flashchromatography (5 to 20% EtOAc in hexanes) to give6-chloro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₅H₂₀BClNO₃ [M+H]⁺ 308.1, found 308.1.

Step c: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (600 mg, 1.4 mmol),6-chloro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(550 mg, 1.8 mmol), K₂CO₃ (500 mg, 3.6 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (300 mg,0.37 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give tert-butyl3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₆ClN₄O₃[M+H]⁺ 535.2.1, found 535.2.

The above tert-butyl3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate was dissolved in dichloromethane (5 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. After the reaction was complete, the solventwas evaporated in vacuo to give3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₉ClN₄O [M+H]⁺ 435.2,found 435.2.

Step d: N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to asuspension of3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (100 mg, 0.21 mmol),2-chloro-5-(trifluoromethyl)pyrimidine (45 mg, 0.25 mmol), and Li₂CO₃(20 mg, 0.27 mmol) in MeCN (10 mL) under magnetic stirring. Theresulting mixture was stirred at 75° C. for 30 min. After cooling toroom temperature, the reaction mixture was diluted with EtOAc, washedwith brine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by preparative TLC (40% EtOAc inhexanes) followed by trituration in MeOH to afford3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 2H), 8.46 (s, 1H), 7.06-7.27 (m, 4H),6.62 (d, J=1.0 Hz, 1H), 6.42-6.49 (m, 1H), 4.83 (s, 2H), 4.36 (t, J=5.7Hz, 2H), 4.00 (s, 3H), 3.03 (t, J=5.7 Hz, 2H), 2.10-2.40 (m, 4H),0.80-1.08 (m, 6H). MS: (ES) m/z calculated for C₃₀H₂₉ClF₃N₆O [M+H]⁺581.2, found 581.2.

Example 2 Synthesis of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: A solution of vinylmagenesium bromide in THE (1 M, 70 mL, 70mmol) was added rapidly to a solution of5-bromo-1-fluoro-2-methyl-3-nitrobenzene (5.0 g, 21.3 mmol) in anhydrousTHF (40 mL) under N₂ and vigorously stirred at −60° C. The reactionmixture was allowed to warm up to −30° C. over 1.5 h. The reaction wasquenched with saturated NH₄Cl solution and the mixture was allowed towarm up to room temperature over 1 h. The reaction mixture was dilutedwith EtOAc, washed with brine, and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (2 to 20% EtOAc in hexanes) to give4-bromo-6-fluoro-7-methyl-1H-indole. MS: (ES) m/z calculated forC₉H₈BrFN [M+H]⁺ 227.9, found 227.9.

Step b: To a suspension of 4-bromo-6-fluoro-7-methyl-1H-indole (1.0 g,4.4 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(2.0 g, 7.9 mmol), and KOAc (2 g, 20.4 mmol) in p-dioxane (12 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (600 mg, 0.73 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for3 h. The reaction mixture was diluted with EtOAc, filtered throughCelite. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (5 to 20% EtOAc inhexanes) to give6-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₅H₂₀BFNO₂ [M+H]⁺ 276.1, found 276.1.

Step c: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(500 mg, 1.2 mmol),6-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(260 mg, 0.94 mmol), K₂CO₃ (500 mg, 3.6 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (100 mg,0.12 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine, and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give tert-butyl2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₆FN₄O₂[M+H]⁺ 503.2, found 503.2.

The above tert-butyl2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate was dissolved in dichloromethane (5 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. After the reaction was complete, the solventwas evaporated in vacuo to give2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₈FN₄ [M+H]⁺ 403.2, found403.2.

Step d: N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to asuspension of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.11 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine(45 mg, 0.25 mmol), and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (5 mL) undermagnetic stirring. The resulting mixture was stirred at 75° C. for 30min. After cooling to room temperature, the reaction mixture was dilutedwith EtOAc, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified byPreparative TLC (40% EtOAc in hexanes) followed by trituration in MeOHto afford2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 2H), 8.17 (s, 1H), 7.18-7.29 (m, 2H),7.05 (d, J=7.8 Hz, 2H), 6.37-6.49 (m, 2H), 4.84 (s, 2H), 4.35 (t, J=5.9Hz, 2H), 3.04 (t, J=5.9 Hz, 2H), 2.34 (d, J=1.5 Hz, 3H), 2.10-2.33 (m,4H), 0.80-1.08 (m, 6H). MS: (ES) m/z calculated C₃₀H₂₉F₄N₆ [M+H]⁺ 549.2,found 549.2.

Example 3 Synthesis of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: A solution of vinylmagenesium bromide in THF (1 M, 60 mL, 60mmol) was added rapidly to a solution of5-bromo-1-chloro-2-methyl-3-nitrobenzene (5.0 g, 20 mmol) in anhydrousTHF (100 mL) under N₂ and vigorously stirred at −40° C. The reactionmixture was stirred at the same temperature for 1.5 h. The reaction wasquenched with saturated NH₄Cl solution and the mixture was allowed towarm up to room temperature over 1 h. The reaction mixture was dilutedwith EtOAc, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (4 to 6% methyl tert-butyl ether/hexane) togive 4-bromo-6-chloro-7-methyl-1H-indole. MS: (ES) m/z calculated forC₉H₈BrClN [M+H]⁺ 243.9, found 243.9.

Step b: To a suspension of 4-bromo-6-chloro-7-methyl-1H-indole (1.0 g,4.1 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(2.0 g, 7.9 mmol), and KOAc (2 g, 20.4 mmol) in p-dioxane (12 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (600 mg, 0.73 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for3 h.

The reaction mixture was diluted with EtOAc, filtered through Celite.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give6-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₅H₂₀BClNO₂ [M+H]⁺ 292.1, found 292.1.

Step c: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(380 mg, 0.87 mmol),6-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(250 mg, 0.86 mmol), K₂CO₃ (290 mg, 2.1 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (160 mg,0.19 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give tert-butyl3-(6-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₆ClN₄O₂[M+H]⁺ 519.2, found 519.2.

The above tert-butyl3-(6-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate was dissolved in dichloromethane (5 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. After the reaction was complete, the solventwas evaporated in vacuo to give3-(6-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₈FN₄ [M+H]⁺ 419.2, found419.2.

Step d: N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to asuspension of3-(6-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (46 mg, 0.10 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine(45 mg, 0.25 mmol), and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (5 mL) undermagnetic stirring. The resulting mixture was stirred at 75° C. for 2 h.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by Preparative TLC(40% EtOAc in hexanes) followed by trituration in MeOH to afford2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 2H), 8.21 (s, 1H), 7.06-7.36 (m, 4H),6.69 (s, 1H), 6.47 (d, J=3.1 Hz, 1H), 4.84 (s, 2H), 4.37 (t, J=5.9 Hz,2H), 3.04 (t, J=5.9 Hz, 2H), 2.34 (s, 3H), 2.10-2.33 (m, 4H), 0.80-1.08(m, 6H). MS: (ES) m/z calculated C₃₀H₂₉ClF₃N₆[M+H]⁺ 565.2, found 565.2.

Example 4 Synthesis of3-(6-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof3-(6-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (46 mg, 0.10 mmol),2,3-difluoro-5-(trifluoromethyl)pyridine (20 mg, 0.11 mmol), and Li₂CO₃(20 mg, 0.27 mmol) in MeCN (5 mL) under magnetic stirring. The resultingmixture was stirred at 75° C. for 2 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withbrine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by Preparative TLC (40% EtOAc inhexanes) followed by trituration in MeOH to afford3-(6-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.16-8.21 (m, 2H), 7.03-7.40 (m, 5H), 6.67 (d,J=0.6 Hz, 1H), 6.48 (dd, J=2.1, 3.3 Hz, 1H), 4.63 (br s, 2H), 4.07 (t,J=5.8 Hz, 2H), 3.11 (t, J=5.8 Hz, 2H), 2.45 (s, 3H), 2.10-2.33 (m, 4H),0.80-1.08 (m, 6H). MS: (ES) m/z calculated C₃₁H₂₉ClF₄N₅[M+H]⁺ 582.2,found 582.2.

Example 5 Synthesis of2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-5-(5-isopropylpyrimidin-2-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of 4-bromo-7-fluoro-1H-indole (1.00 g, 4.67mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.31g, 5.14 mmol) and KOAc (1.15 g, 11.7 mmol) in dioxane (15 mL) was addedPd(dppf)Cl₂.CH₂Cl₂ (416 mg, 0.51 mmol). The reaction mixture wasdegassed (N₂) for 2 min and stirred at 100° C. for 2 h. The reactionmixture was cooled to room temperature, diluted with EtOAc and filteredthrough Celite. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (0 to 30% EtOAcin hexanes) to give7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. MS:(ES) m/z calculated for C₁₄H₁₈BFNO₂ [M+H]⁺ 262.1, found 262.1.

Step b: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(490 mg, 1.13 mmol),7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (350mg, 1.34 mmol), and K₂CO₃ (830 mg, 6.78 mmol) in p-dioxane (12 mL) andwater (3 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (200 mg,0.32 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature, diluted with EtOAc, washed with aqueous NaHCO₃ and driedover Na₂SO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (0 to 40% EtOAcin hexanes) to give tert-butyl3-(7-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₅FN₄O₂ [M+H]⁺ 489.3, found 489.3.

The above tert-butyl3-(7-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(0.350 g, 0.71 mmol) was dissolved in dichloromethane (5 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. The solvent was evaporated in vacuo to give3-(7-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₄H₂₆FN₄ [M+H]⁺ 389.2, found389.2.

Step c: Triethylamine (0.13 mL, 0.93 mmol) was added to a suspension of3-(7-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (0.040 g, 0.094 mmol), 2-chloro-5-isopropylpyrimidine (70mg, 0.44 mmol) and Li₂CO₃ (0.143 g, 1.76 mmol) in DMSO (1.5 mL). Theresulting mixture was stirred at 110° C. for 3 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withaqueous NaHCO₃ and dried over Na₂SO₄. The solvent was removed underreduced pressure and the residue was purified by silica gel flashchromatography (0 to 40% EtOAc in hexanes) to afford2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-5-(5-isopropylpyrimidin-2-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.86 (br s, 1H), 8.49 (s, 2H), 7.20 (t, J=7.6Hz, 1H), 7.15 (t, J=2.6 Hz, 1H), 7.02 (d, J=6.8 Hz, 2H), 6.64 (m, 1H),6.51 (m, 2H), 4.75 (s, 2H), 4.30 (br s, 2H), 3.03 (t, J=5.8 Hz, 2H),2.76 (septet, J=7.0 Hz, 1H), 2.10-2.40 (two br, 4H), 1.21 (d, J=7.2 Hz,6H), 0.98 (br s, 6H). MS: (ES) m/z calculated for C₃₁H₃₄FN₆ [M+H]⁺509.3, found 509.3.

Example 6 Synthesis of5-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

To a suspension of3-bromo-2-(2,6-diethylphenyl)-5-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine(60 mg, 0.12 mmol),7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (60mg, 0.24 mmol) and K₂CO₃ (180 mg, 1.30 mmol) in p-dioxane (3.2 mL) andwater (0.6 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (80mg, 0.098 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 2 h. The reaction mixture was cooled toroom temperature, diluted with EtOAc, washed with brine and dried overNa₂SO₄. The solvent was removed under reduced pressure. The obtainedresidue was purified by silica gel flash chromatography (0-100%DCM/hexanes followed by 0 to 40% EtOAc in hexanes) followed bypreparative HPLC to yield5-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 11.31 (br s, 1H), 8.36 (d, J=1.2 Hz, 1H), 7.97(d, J=2.0 Hz, 1H), 7.39 (m, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.11 (br s,2H), 6.64 (m, 1H), 6.52 (m, 1H), 6.45 (t, J=3.2 Hz, 1H), 4.47 (br s,2H), 3.98 (t, J=5.6 Hz, 2H), 3.15 (t, J=5.6 Hz, 2H), 2.31 (br s, 4H),1.01 (br s, 6H). MS: (ES) m/z calculated for C₃₀H₂₇ClF₄N₅[M+H]⁺ 568.2,found 568.2.

Example 7 Synthesis of5-(3,5-dichloro-2-pyridyl)-2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: A mixture of3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (100 mg, 0.27 mmol), 3,5-dichloro-2-fluoro-pyridine (150mg, 0.90 mmol), Li₂CO₃ (200 mg, 2.7 mmol) and NEt₃ (0.20 mL, 1.42 mmol)in DMSO (3 mL) was stirred at 100° C. for 3 h. It was then cooled toroom temperature, diluted with EtOAc and water. The organic layer wasseparated, dried over Na₂SO₄, concentrated on a rotary evaporator underreduced pressure and purified by silica gel flash chromatography (0 to30% EtOAc in hexanes) to afford3-bromo-5-(3,5-dichloro-2-pyridyl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.

Step b: To a suspension of3-bromo-5-(3,5-dichloro-2-pyridyl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine(60 mg, 0.12 mmol),7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (63mg, 0.24 mmol), and K₂CO₃ (140 mg, 1.0 mmol) in p-dioxane (3 mL) andwater (0.6 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (60mg, 0.073 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 2 h. The reaction mixture was cooled toroom temperature, diluted with EtOAc, washed with brine and dried overNa₂SO₄. The solvent was removed under reduced pressure. The obtainedresidue was purified by silica gel flash chromatography (0 to 100%DCM/hexanes followed by 0 to 35% EtOAc in hexanes) followed bypreparative HPLC to yield5-(3,5-dichloro-2-pyridyl)-2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD-CDCl₃) δ 11.03 (br s, 1H), 8.02 (d, J=2.4 Hz,1H), 7.68 (d, J=2.0 Hz, 1H), 7.30 (t, J=2.6 Hz, 1H), 7.21 (t, J=7.6 Hz,1H), 7.06 (br s, 2H), 6.59 (m, 1H), 6.47 (t, J=8.0, 1H), 6.44 (m, 1H),4.29 (br s, 2H), 3.78 (t, J=5.6, 2H), 3.09 (t, J=5.6, 2H), 2.10-2.42 (2br s, 4H), 0.399 (br s, 6H). MS: (ES) m/z calculated for C₂₉H₂₇Cl₂FN₅[M+H]⁺ 534.2, found 534.2.

Example 8 Synthesis of2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: tert-Butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(400 mg, 0.92 mmol) was dissolved in dichloromethane (4 mL) and chargedwith HCl in dioxane (4N, 6 mL). The resulting mixture was stirred atroom temperature for 1.5 h. The solvent was evaporated in vacuo to give3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride.

Step b: A mixture of3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (100 mg, 0.27 mmol),2,3-difluoro-5-(trifluoromethyl)pyridine (100 mg, 0.54 mmol) and K₂CO₃(150 mg, 1.08 mmol) in CH₃CN (3 mL) was stirred at 80° C. for 2 h. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 30% EtOAc in hexanes) to afford3-bromo-2-(2,6-diethylphenyl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.MS: (ES) m/z calculated for C₂₂H₂₂BrF₄N₄[M+H]⁺ 497.1, found 497.1.

Step c: To a suspension of3-bromo-2-(2,6-diethylphenyl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine(60 mg, 0.12 mmol),7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (45mg, 0.17 mmol), and K₂CO₃ (120 mg, 0.86 mmol) in p-dioxane (3 mL) andwater (0.6 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (120mg, 0.15 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 1 h. The reaction mixture was cooled toroom temperature, diluted with EtOAc, washed with brine, and dried overNa₂SO₄. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (0 to 100% DCM inhexanes followed by 0 to 50% EtOAc in hexanes) to give2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.70 (br s, 1H), 8.19 (s, 1H), 7.39 (dd, J=2,13 Hz, 1H), 7.20 (m, 2H), 7.03 (d, J=7.2 Hz, 2H), 6.67 (m, 1H), 6.52 (m,2H), 4.64 (br s, 2H), 4.07 (t, J=5.6 Hz, 2H), 3.12 (t, J=5.6 Hz, 2H),2.1-2.4 (two br s, 4H), 0.98 (br s, 6H). MS: (ES) m/z calculated forC₃₀H₂₇F₅N₅ [M+H]⁺ 552.2, found 552.2.

Example 9 Synthesis of2-(2,6-diethylphenyl)-3-(7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of 4-bromo-7-methoxy-1H-indole (800 mg, 3.5mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.6g, 6.3 mmol), and KOAc (1.6 g, 16.3 mmol) in p-dioxane (10 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (800 mg, 0.97 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for3 h. The reaction mixture was diluted with EtOAc, filtered throughCelite. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (5 to 25% EtOAc inhexanes) to give7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. MS:(ES) m/z calculated for C₁₅H₂₁BNO₃ [M+H]⁺ 274.2, found 274.2.

Step b: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(300 mg, 0.72 mmol),7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (200mg, 0.73 mmol), and K₂CO₃ (300 mg, 2.2 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (100 mg,0.12 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give tert-butyl2-(2,6-diethylphenyl)-3-(7-methoxy-1H-indol-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₇N₄O₃ [M+H]⁺ 501.2, found 501.2.

The above tert-butyl2-(2,6-diethylphenyl)-3-(7-methoxy-1H-indol-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylatewas dissolved in dichloromethane (5 mL) and charged with HCl in dioxane(4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the reaction was complete, the solvent was evaporated in vacuoto give2-(2,6-diethylphenyl)-3-(7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₉N₄O [M+H]⁺ 401.2, found401.2.

Step c: N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to asuspension of2-(2,6-diethylphenyl)-3-(7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.11 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine(50 mg, 0.27 mmol), and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (10 mL) undermagnetic stirring. The resulting mixture was stirred at 75° C. for 1 h.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by Preparative TLC(40% EtOAc in hexanes) followed by trituration in MeOH to afford2-(2,6-diethylphenyl)-3-(7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydr-2H-pyrazolo[4,3-c]pyridine.

¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 2H), 8.18 (dt, J=1.0, 2.0 Hz, 2H),7.37 (dd, J=2.0, 13.2 Hz, 1H), 7.03-7.30 (m, 4H), 6.54 (dd, J=0.8, 8.0Hz, 1H), 6.37-6.49 (m, 2H), 4.65 (s, 2H), 4.07 (t, J=5.8 Hz, 2H), 3.88(s, 3H), 3.11 (t, J=5.8 Hz, 2H), 2.10-2.35 (br m, 4H), 0.85-1.03 (br m,6H). MS: (ES) m/z calculated C₃₀H₃₀F₃N₆O [M+H]⁺ 547.2, found 547.2.

Example 10 Synthesis of2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof2-(2,6-diethylphenyl)-3-(7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.11 mmol),2,3-difluoro-5-(trifluoromethyl)pyridine (60 mg, 0.33 mmol), and Li₂CO₃(20 mg, 0.27 mmol) in MeCN (5 mL) under magnetic stirring. The resultingmixture was stirred at 80° C. for 2 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withbrine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by Preparative TLC (40% EtOAc inhexanes) followed by trituration in MeOH to afford2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=11.4 Hz, 2H), 7.16-7.31 (m, 4H),7.02 (d, J=7.7 Hz, 1H), 6.40-6.55 (m, 3H), 4.85 (s, 2H), 4.36 (t, J=5.9Hz, 2H), 3.89 (s, 3H), 3.03 (t, J=5.9 Hz, 2H), 2.10-2.35 (br m, 4H),0.85-1.03 (br m, 6H). MS: (ES) m/z calculated C₃₁H₃₀F₄N₅O [M+H]⁺ 564.2,found 564.2.

Example 11 Synthesis of3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(1.5 g, 3.6 mmol), was dissolved in dichloromethane (10 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. After the reaction was complete, the solventwas evaporated in vacuo to give3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₁₆H₂₁BrN₃ [M+H]⁺ 334.1,found 334.1.

N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspensionof3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (750 mg, 2.02 mmol),2,3-difluoro-5-(trifluoromethyl)pyridine (800 mg, 4.37 mmol), and K₂CO₃(800 mg, 5.79 mmol) in MeCN (10 mL) under magnetic stirring. Theresulting mixture was stirred at 85° C. for 2 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withbrine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by silica gel flash chromatography(2 to 15% EtOAc in hexanes) to afford3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.MS: (ES) m/z calculated for C₂₂H₂₂BrF₄N₄[M+H]⁺ 497.1, found 497.1.

Step b. To a suspension of3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(50 mg, 0.1 mmol),7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (50mg, 0.18 mmol), and K₂CO₃ (180 mg, 1.3 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (40 mg,0.05 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.18 (s, 1H), 7.04-7.43 (m, 5H),6.97 (d, J=7.9 Hz, 1H), 6.52-6.59 (m, 2H), 4.63 (s, 2H), 4.07 (t, J=5.8Hz, 2H), 3.11 (t, J=5.8 Hz, 2H), 2.10-2.40 (m, 4H), 0.80-1.08 (m, 6H).MS: (ES) m/z calculated C₃₀H₂₇ClF₄N₅[M+H]⁺ 568.2, found 568.2.

Example 12 Synthesis of2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(5-fluoro-7-methyl-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: A solution of vinylmagenesium bromide in THF (1 M, 66 mL, 66mmol) was added rapidly to a solution of1-bromo-2-fluoro-4-methyl-5-nitrobenzene (5.0 g, 21.4 mmol) in anhydrousTHF (50 mL) under N₂ and vigorously stirring at −60° C. The reactionmixture was stirred at the same temperature and allowed to warm to −35°C. over 1.5 h. The reaction was quenched with saturated NH₄Cl solutionand the mixture was allowed to warm up to room temperature over 1 h. Thereaction mixture was diluted with EtOAc, washed with brine and driedover MgSO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (2 to 20% EtOAcin hexanes) to give 4-bromo-5-fluoro-7-methyl-1H-indole. MS: (ES) m/zcalculated for C₉H₈BrFN [M+H]⁺ 227.9, found 227.9.

Step b: To a suspension of 4-bromo-5-fluoro-7-methyl-1H-indole (1.6 g,7.0 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(3.2 g, 12.6 mmol), and KOAc (3 g, 30.6 mmol) in p-dioxane (10 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (800 mg, 0.97 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 95° C. for 5h. The reaction mixture was diluted with EtOAc, filtered through Celite.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 30% EtOAc in hexanes)to give5-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₅H₂₀BFNO₂ [M+H]⁺ 276.2, found 276.2.

Step c: To a suspension of3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(80 mg, 0.16 mmol),5-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(80 mg, 0.29 mmol), and K₂CO₃ (180 mg, 1.3 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (40 mg,0.05 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)followed by HPLC (MeCN/H₂O, with 1% TFA) to give2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(5-fluoro-7-methyl-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.13-8.20 (m, 2H), 7.38 (dd, J=2.0 Hz,13.0,1H), 7.10-7.29 (m, 3H), 6.84-6.91 (m, 1H), 6.60 (dd, J=0.9, 10.8Hz, 1H), 6.39 (dd, J=2.1 3.2 Hz, 1H), 4.75 (d, J=15.7 Hz, 1H), 4.45 (d,J=15.7 Hz, 1H), 4.02-4.09 (m, 2H), 3.12 (t, J=5.8, 2H), 2.41-2.54 (m,2H), 2.43 (s, 3H), 1.96-2.21 (m, 2H), 1.22 (t, J=7.5 Hz, 3H), 0.75 (t,J=7.5 Hz, 3H). MS: (ES) m/z calculated C₃₁H₂₉F₅N₅ [M+H]⁺ 566.2, found566.2.

Example 13 Synthesis of3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(500 mg, 1.2 mmol),7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (400mg, 1.44 mmol), and K₂CO₃ (500 mg, 3.6 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (200 mg,0.24 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 35% EtOAc in hexanes)to give tert-butyl3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. MS: (ES) m/z calculated for C₂₉H₃₄ClN₄O₂[M+H]⁺ 505.2,found 505.2.

The above tert-butyl3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate was dissolved in dichloromethane (5 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. After the reaction was complete, the solventwas evaporated in vacuo to give3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₈FN₄ [M+H]⁺ 403.2, found403.2.

Step b: N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to asuspension of3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.11 mmol), 2-fluoro-5-(trifluoromethyl)pyridine(50 mg, 0.31 mmol), and Li₂CO₃ (20 mg, 0.27 mmol) in MeCN (5 mL) undermagnetic stirring. The resulting mixture was stirred at 85° C. for 5 h.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by Preparative TLC(40% EtOAc in hexanes) followed by trituration in MeOH to afford3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.29-8.37 (m, 2H), 7.70 (ddt, J=0.6, 2.6, 9.1Hz, 1H), 7.46 (d, J=3.2 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.11 (br, 2H),6.84-6.93 (m, 2H), 6.51-6.55 (m, 2H), 4.65 (s, 2H), 4.19 (t, J=5.8 Hz,2H), 3.01 (t, J=5.8 Hz, 2H), 2.10-2.33 (br,m, 4H), 0.80-1.08 (br,m, 6H).MS: (ES) m/z calculated C₃₀H₂₈ClF₃N₅[M+H]⁺ 550.2, found 550.2.

Example 14 Synthesis of3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (25 mg, 0.06 mmol),2-chloro-3-methyl-5-(trifluoromethyl)pyridine (40 mg, 0.20 mmol), andLi₂CO₃ (20 mg, 0.27 mmol) in DMSO (5 mL) under magnetic stirring. Theresulting mixture was stirred at 155° C. for 6 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withbrine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by HPLC (MeCN/H₂O, with 0.1% TFA)to afford3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 8.31 (dt, J=0.9, 1.7 Hz, 1H),7.57 (tt, J=0.8, 1.7 Hz, 1H), 7.19-7.29 (m, 2H), 7.04 (d, J=7.7 Hz, 2H),6.95 (dd, J=0.7, 7.7 Hz, 1H), 6.51-6.57 (m, 2H), 4.32 (s, 2H), 3.66 (t,J=5.8 Hz, 2H), 3.14 (t, J=5.8 Hz, 2H), 2.40 (s, 3H), 2.10-2.38 (br,m,4H), 0.88-1.08 (br,m, 6H). MS: (ES) m/z calculated C₃₁H₃₀ClF₃N₅[M+H]⁺564.2, found 564.2.

Example 15 Synthesis of3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (25 mg, 0.06 mmol), 2-chloro-5-(trifluoromethoxy)pyridine(30 mg, 0.15 mmol), and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (5 mL) undermagnetic stirring. The resulting mixture was stirred at 155° C. for 4 h.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by HPLC (MeCN/H₂O,with 1% TFA) to afford3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethoxy)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.09 (dd, J=1.0, 2.9 Hz, 1H),7.02-7.34 (m, 5H), 6.98 (dd, J=8.0 Hz, 1H), 6.54-6.66 (m, 3H), 4.50 (s,2H), 4.11 (t, J=5.8 Hz, 2H), 3.05 (t, J=5.8 Hz, 2H), 2.14-2.32 (br,m,4H), 0.88-1.08 (br,m, 6H). MS: (ES) m/z calculated C₃₀H₂₈ClF₃N₅O [M+H]⁺566.2, found 566.2.

Example 16 Synthesis of3-(7-chloro-1H-indol-4-yl)-5-(3-chloro-5-fluoropyridin-2-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (45 mg, 0.10 mmol), 3-chloro-2,5-difluoropyridine (60 mg,0.40 mmol), and K₂CO₃ (100 mg, 0.72 mmol) in DMSO (5 mL) under magneticstirring. The resulting mixture was stirred at 120° C. for 6 h. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by HPLC (MeCN/H₂O,with 0.1% TFA) to afford3-(7-chloro-1H-indol-4-yl)-5-(3-chloro-5-fluoropyridin-2-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 8.00 (dd, J=0.5, 2.7 Hz, 1H),7.45 (dd, J=2.7, 7.5 Hz, 1H), 7.19-7.30 (m, 2H), 7.03 (br, 2H), 6.95 (d,J=7.9 Hz, 1H), 6.52-6.60 (m, 2H), 4.26 (s, 2H), 3.72 (t, J=5.8 Hz, 2H),3.15 (t, J=5.8 Hz, 2H), 2.17-2.35 (br,m, 4H), 0.88-1.08 (br,m, 6H). MS:(ES) m/z calculated C₂₉H₂₇Cl₂FN₅ [M+H]⁺ 534.2, found 534.2.

Example 17 Synthesis of3-(7-chloro-1H-indol-4-yl)-5-(5-cyclopropyl-3-fluoro-2-pyridyl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: A mixture of 5-bromo-2,3-difluoropyridine (1.70 g, 8.76 mmol),cyclopropylboronic acid (1.10 g, 12.8 mmol), Cs₂CO₃ (12.0 g, 36.9 mmol)and Pd(dppf)Cl₂ complex with dichloromethane (250 mg, 0.30 mmol) intoluene (22 mL) and water (2 mL) was stirred at 105° C. for 1.5 h undera N₂ atmosphere. It was then cooled to room temperature and diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 100% DCM/hexanes) to give5-cyclopropyl-2,3-difluoro-pyridine. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d,J=2.0 Hz, 1H), 7.02 (m, 1H), 1.77 (m, 1H), 0.91 (m, 2H), 0.54 (m, 2H).

Step b: A mixture of3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (40 mg, 0.090 mmol), NEt₃ (0.15 mL, 1.07 mmol),5-cyclopropyl-2,3-difluoro-pyridine (120 mg, 0.77 mmol) and Li₂CO₃ (120mg, 1.62 mmol) in DMSO (2 mL) was stirred at 120° C. overnight. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 40% EtOAc in hexanes) to afford3-(7-chloro-1H-indol-4-yl)-5-(5-cyclopropyl-3-fluoro-2-pyridyl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.44 (br s, 1H), 7.66 (s, 1H), 7.07 (m, 2H),6.89 (m, 2H), 6.78 (m, 2H), 6.42 (m, 2H), 4.26 (br s, 2H), 3.69 (t,J=5.8 Hz, 2H), 2.96 (t, J=5.8 Hz, 2H), 2.00-2.30 (m, 4H), 1.66 (m, 1H),0.86 (br s, 6H), 0.78 (m, 2H), 0.45 (m, 2H). MS: (ES) m/z calculated forC₃₂H₃₂ClFN₅ [M+H]⁺ 540.2, found 540.2.

Example 18 Synthesis of2-[2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidin-5-yl]propan-2-ol

Step a: A mixture of3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (75 mg, 0.17 mmol), methyl2-chloropyrimidine-5-carboxylate (60 mg, 0.34 mmol) and NEt₃ (0.12 mL,0.85 mmol) in CH₃CN (2 mL) was stirred at 80° C. for 15 min. It was thencooled to room temperature, diluted with EtOAc, washed with aqueousNaHCO₃ and dried over Na₂SO₄. The solvent was removed under reducedpressure and the residue was purified by silica gel flash chromatography(0 to 60% EtOAc in hexanes) to afford methyl2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₀ClN₆O₂[M+H]⁺ 541.2, found 541.2.

Step b: To a solution of methyl2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylate(35 mg, 0.064 mmol) in THF (2 mL) was added CH₃Li (0.25 mL, 0.40 mmol,1.6 M in ether) at 0° C. The obtained mixture was stirred at the sametemperature for 20 min, quenched with saturated NH₄Cl, and extractedwith EtOAc. The organic layer was separated, washed with aqueous NaHCO₃,dried over Na₂SO₄, concentrated under reduced pressure and purified bysilica gel flash chromatography (0 to 100% EtOAc in hexanes) to afford2-[2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidin-5-yl]propan-2-ol.¹H NMR (400 MHz, CDCl₃) δ 8.41 (br s, 1H), 8.30 (m, 2H), 7.13 (m, 2H),7.06 (t, J=7.6 Hz, 1H), 6.88 (m, 2H), 6.80 (d, J=8.4 Hz, 1H), 6.40 (m,2H), 4.63 (br s, 2H), 4.16 (br s, 2H), 2.88 (t, J=5.8, 2H), 2.1 (m, 4H),1.41 (m, 6H), 0.85 (br s, 6H). MS: (ES) m/z calculated for C₃₁H₃₄ClN₆O[M+H]⁺ 541.2, found 541.2.

Example 19 Synthesis of2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxamide

Step a: A mixture of methyl2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylate(40 mg, 0.074 mmol) (intermediate from Example 9) and LiOH.H₂O (100 mg,2.5 mmol) in a mixed solvent of MeOH (1.2 mL), THF (1.2 mL) and water(0.6 mL) was stirred at 45° C. for 1 h. It was then cooled to roomtemperature, acidified with 1 M aqueous HCl and extracted with EtOAc.The organic layer was separated, dried over Na₂SO₄ and concentratedunder reduced pressure to give2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylicacid.

Step b: To a mixture of2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylicacid (35 mg, 0.66 mmol) and HATU (100 mg, 0.26 mmol) in DMF (5 mL) wasadded ammonia in dioxane (0.5 M, 1 mL, 0.5 mmol). After stirring for 15min, the reaction mixture was quenched with water and extracted withEtOAc. The organic layer was separated, dried over Na₂SO₄, concentratedunder reduced pressure and purified by silica gel flash chromatography(0 to 100% EtOAc in hexanes) to yield2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxamide.¹H NMR (400 MHz, CD₃OD-CDCl₃) δ 8.74 (br s, 1H), 7.93 (s, 1H), 7.47 (m,1H), 7.34 (d, J=3.2 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.02 (d, J=6.0 Hz,2H), 6.90 (d, J=7.6 Hz, 1H), 6.48 (d, J=7.6 Hz, 1H), 6.45 (d, J=3.6 Hz,1H), 4.81 (br s, 2H), 4.49 (br s, 4H), 4.35 (br s, 2H), 2.10-2.40 (m,4H), 0.91 (br s, 6H). MS: (ES) m/z calculated for C₂₉H₂₉ClN₇O [M+H]⁺526.2, found 526.2.

Example 20 Synthesis of2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-5-methyl-pyrimidine-4-carboxylicacid

A mixture of3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (25 mg, 0.056 mmol),2-chloro-5-methyl-pyrimidine-4-carboxylic acid (60 mg, 0.34 mmol),Li₂CO₃ (120 mg, 1.6 mmol) and NEt₃ (0.12 mL, 0.86 mmol) in DMSO (1.5 mL)was stirred at 120° C. for 3 h. It was then cooled to room temperature,diluted with EtOAc, and extracted with 10% aqueous HCl. The organiclayer was separated, dried over Na₂SO₄, concentrated on a rotaryevaporator under reduced pressure and purified by preparative HPLC toafford2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-5-methyl-pyrimidine-4-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 11.27 (br s, 1H), 8.43 (br s, 1H), 7.52(s, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.18 (d, J=3.6 Hz, 2H), 6.98 (d, J=7.6Hz, 1H), 6.66 (d, J=3.2 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 4.90 (m, 2H),4.39 (t, J=5.6 Hz, 2H), 3.06 (t, J=5.6 Hz, 6H), 2.38 (m, 7H), 1.06 (brs, 6H). MS: (ES) m/z calculated for C₃₀H₃₀ClN₆O₂[M+H]⁺ 541.2, found541.2.

Example 21 Synthesis of[2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-5-methyl-pyrimidin-4-yl]methanol

Step a: A mixture of2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-5-methyl-pyrimidine-4-carboxylicacid (12 mg, 0.022 mmol) and conc. H₂SO₄ (0.40 mL) in MeOH (5 mL) wasrefluxed for 1 h. It was then cooled to room temperature, basicifiedwith saturated NaHCO₃ and extracted EtOAc. The organic layer wasseparated, dried over Na₂SO₄, concentrated on a rotary evaporator underreduced pressure to obtain methyl2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-5-methyl-pyrimidine-4-carboxylate.

Step b: The above methyl2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-5-methyl-pyrimidine-4-carboxylate(10 mg, 0.020 mmol) was dissolved in THF (2 mL) and charged with LiAlH₄in THF (1 M, 0.07 mL, 0.14 mmol) at 0° C. The resulting mixture wasstirred at 0° C. for 20 min. It was then quenched with MeOH, dilutedwith EtOAc, washed with brine and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 80% EtOAc in hexanes) to give[2-[3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-5-methyl-pyrimidin-4-yl]methanol.¹H NMR (400 MHz, CDCl₃) δ 8.38 (br s, 1H), 7.91 (s, 1H), 7.33 (br s,1H), 7.07 (t, J=7.6 Hz, 1H), 6.90 (br s, 2H), 6.81 (d, J=7.6 Hz, 1H),6.44 (br s, 1H), 6.40 (d, J=7.6 Hz, 1H), 4.68 (br s, 2H), 4.42 (d, J=4.2Hz, 2H), 4.20 (t, J=4.4 Hz, 1H), 4.15 (s, 2H), 2.89 (t, J=5.6 Hz, 2H),2.00-2.30 (2 br s, 4H), 1.87 (s, 3H), 0.85 (6H). MS: (ES) m/z calculatedfor C₃₀H₃₂ClN₆O [M+H]⁺ 527.2, found 527.2.

Example 22 Synthesis of3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-N-phenyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (45 mg, 0.10 mmol), and phenyl isocyanate (0.1 mL, 0.92mmol) in THF (5 mL) under magnetic stirring. The resulting mixture wasstirred at 50° C. for 1 h and quenched with MeOH. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withaqueous NaHCO₃ solution, brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified byPreparative TLC (40% EtOAc in hexanes) followed by HPLC (MeCN/H₂O, with1% TFA) to afford3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-N-phenyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide.¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 7.21-7.40 (m, 5H), 6.98-7.10 (m,4H), 6.50-6.61 (m, 2H), 6.35 (s, 1H), 4.50 (s, 2H), 3.98 (t, J=5.9 Hz,2H), 3.05 (t, J=5.9 Hz, 2H), 2.17-2.35 (br,m, 4H), 0.88-1.08 (br,m, 6H).MS: (ES) m/z calculated C₃₁H₃₁ClN₅O [M+H]⁺ 524.2, found 524.2.

Example 23 Synthesis of(4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indol-7-yl)methanol

Step a: To a suspension of methyl 4-bromo-1H-indole-7-carboxylate (300mg, 1.18 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (330 mg,1.30 mmol), and KOAc (290 mg, 2.96 mmol) in p-dioxane (8 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (100 mg, 0.12 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for1 h. The reaction mixture was diluted with EtOAc, filtered throughCelite. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (5 to 30% EtOAc inhexanes) to give methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate.MS: (ES) m/z calculated for C₁₆H₂₁BNO₄ [M+H]⁺ 302.2, found 302.2.

Step b: To a suspension of3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(100 mg, 0.20 mmol), methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate(100 mg, 0.33 mmol), and K₂CO₃ (180 mg, 1.3 mmol) in p-dioxane (6 mL)and water (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (50mg, 0.06 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 3 h. The reaction mixture was dilutedwith EtOAc, filtered through Celite, washed with brine and dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (5 to 35% EtOAc inhexanes) to give methyl4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxylate.MS: (ES) m/z calculated C₃₂H₃₀F₄N₅O₂[M+H]⁺ 592.2, found 592.2.

Step c: To a solution of methyl4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxylate(25 mg, 0.04 mmol) in anhydrous THF (6 mL) under ice bath was added asolution of LiAlH₄ in THF (2M, 0.3 mL, 0.6 mmol). The reaction mixturestirred at 0° C. for 30 min and then quenched with MeOH. The reactionmixture was diluted with EtOAc, washed with aqueous NaHCO₃ solution,brine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by HPLC (MeCN/H₂O, with 0.1% TFA)to give(4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indol-7-yl)methanol.¹H NMR (400 MHz, CD₃OD) δ 8.20 (dt, J=1.0, 1.9 Hz, 1H), 7.63 (dd, J=2.1,13.5 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.24 (t, J=7.7 Hz, 1H), 7.08 (s,2H), 6.89 (d, J=7.4 Hz, 1H), 6.57 (d, J=7.4 Hz, 1H), 6.45 (dd, J=0.6,3.2 Hz, 1H), 4.83-4.89 (m, 4H), 4.63 (s, 2H), 4.11 (t, J=5.7 Hz, 2H),3.06 (t, J=5.7 Hz, 2H), 2.11-2.46 (m, 4H), 0.85-1.08 (m, 6H). MS: (ES)m/z calculated C₃₁H₃₀F₄N₅O [M+H]⁺ 564.2, found 564.2.

Example 24 Synthesis of4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxamide

Step a: To a solution of methyl4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxylate(25 mg, 0.04 mmol) in MeOH (5 mL) and water (1 mL) was added LiOHmonhydrate (100 mg, 2.38 mmol). The reaction mixture stirred at 60° C.for 2 h and quenched with 1 N HCl. The reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure to give4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxylicacid. MS: (ES) m/z calculated C₃₁H₂₈F₄N₅O₂[M+H]⁺ 578.2, found 578.2.

Step b: To a solution of the above4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxylicacid in DMF (5 mL) was charged with HATU (50 mg, 0.13 mmol), DIEA (0.2mL, 1.15 mmol) and followed by ammonia in dioxane (0.5 M, 1 mL, 0.5mmol). The reaction mixture stirred at room temperature for 2 h. Thereaction mixture was diluted with EtOAc, washed with brine and driedover MgSO₄. The solvent was removed under reduced pressure and theresidue was purified by HPLC (MeCN/H₂O, with 1% TFA) to give4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxamide.¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, J=2.1 Hz, 1H), 7.64 (dd, J=2.0, 13.5Hz, 1H), 7.49 (d, J=3.2 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.7Hz, 1H), 7.11 (br, 2H), 6.62 (d, J=7.8 Hz, 1H), 6.53 (d, J=3.2 Hz, 1H),4.67 (s, 2H), 4.13 (t, J=5.8 Hz, 2H), 3.25-3.34 (br s, 3H) 3.07 (t,J=5.8 Hz, 2H), 2.11-2.44 (m, 4H), 0.87-1.08 (m, 6H). MS: (ES) m/zcalculated C₃₁H₂₉F₄N₆O [M+H]⁺ 577.2, found 577.2.

Example 25 Synthesis of4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxamide

Step a: To a solution of methyl4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxylate(25 mg, 0.04 mmol) in THF (5 mL) under ice bath was added methyllithiumsolution in THF (3 M, 0.2 mL, 0.6 mmol). The reaction mixture stirred at0° C. for 15 min and quenched with MeOH. The reaction mixture wasdiluted with EtOAc, washed with brine and dried over MgSO₄. The solventwas removed under reduced pressure and the residue was purified byPreparative TLC (45% EtOAc in hexanes) followed by HPLC (MeCN/H₂O, with1% TFA) to give4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indole-7-carboxamide.¹H NMR (400 MHz, CDCl₃) δ 9.54 (s, 1H), 8.18 (dt, J=1.0, 2.1 Hz, 1H),7.38 (dd, J=2.0, 13.2 Hz, 1H), 7.03-7.39 (m, 5H), 6.75 (d, J=7.6 Hz,1H), 6.46-6.55 (m, 2H), 4.65 (br s, 2H), 4.07 (t, J=5.8 Hz, 2H), 3.11(t, J=5.8 Hz, 2H), 2.14-2.32 (br m, 4H), 1.67 (s, 6H), 1.57 (br s, 1H),0.88-1.28 (br m, 6H). MS: (ES) m/z calculated C₃₃H₃₄F₄N₅O [M+H]⁺ 592.2,found 592.2.

Example 26 Synthesis of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: Vinylmagnesium bromide solution in THF (1 M, 70 mL, 70 mmol) wasadded to a solution of 4-bromo-2-fluoro-6-nitroanisole (5.0 g, 20 mmol)in anhydrous THF (70 mL) under N₂ at −50° C. The reaction mixture wasstirred at the same temperature and allowed to warm to −30° C. over 1.5h. The reaction mixture was quenched with saturated aqueous NH₄Clsolution and allowed to warm up to room temperature over 1 h. Thereaction mixture was diluted with EtOAc, washed with brine and driedover Na₂SO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (0 to 100% EtOAcin hexanes) to yield 4-bromo-6-fluoro-7-methoxy-1H-indole. MS: (ES) m/zcalculated for C₉HBrFNO [M+H]⁺ 243.9, found 243.9.

Step b: To a suspension of 4-bromo-6-fluoro-7-methoxy-1H-indole (900 mg,3.68 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(1.21 g, 4.8 mmol) and and KOAc (1.08 g, 11 mmol) in dioxane (16 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (400 mg, 0.49 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for2 h. The reaction mixture was diluted with EtOAc and filtered throughCelite. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (0 to 100% EtOAc inhexanes) to give6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₅H₂₀BFNO₃ [M+H]⁺292.1, found 292.1.

Step c: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(380 mg, 0.87 mmol),6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(230 mg, 0.79 mmol) and K₂CO₃ (445 mg, 3.22 mmol) in p-dioxane (8 mL)and water (1.2 mL) was added Pd(dppf)Cl₂ complex with dichloromethane(150 mg, 0.18 mmol). The reaction mixture was degassed (N₂) for 2 minand stirred under N₂ at 100° C. for 2.5 h. The reaction mixture wasdiluted with EtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (0 to 70% EtOAc in hexanes)to give tert-butyl3-(6-fluoro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₆FN₄O₃[M+H]⁺ 519.2, found 519.2.

The above tert-butyl3-(6-fluoro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(290 mg, 0.56 mmol) was dissolved in dichloromethane (2 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. After the reaction was complete, the solventwas evaporated in vacuo to give3-(6-fluoro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₈FN₄O [M+H]⁺ 419.2,found 419.2.

Step d: Triethylamine (0.42 mL, 3 mmol) was added to a suspension of3-(6-fluoro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (350 mg, 0.77 mmol) and2-chloro-5-(trifluoromethyl)pyrimidine (183 mg, 1.0 mmol) in MeCN (8mL). The resulting mixture was stirred at 80° C. for 45 min. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 60% EtOAc in hexanes) to afford3-(6-fluoro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.47 (two br s, 3H), 7.20-7.27 (m, 2H), 7.05(d, J=7.6 Hz, 2H), 6.61 (s, 1H), 6.40-6.50 (m, 2H), 4.83 (br s, 2H),4.36 (t, J=5.8 Hz, 2H), 4.06 (d, J=2.4 Hz, 2H), 3.03 (t, J=5.8 Hz, 2H),2.26 (m, 4H), 1.00 (m, 6H). MS: (ES) m/z calculated for C₃₀H₂₉F₄N₆O[M+H]⁺ 565.2, found 565.2.

Example 27 Synthesis of[4-[2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanol

Step a: Vinylmagnesium bromide solution in THF (1 M, 341 mL, 341 mmol)was added to a solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (15.0 g,56.8 mmol) in anhydrous THF (200 mL) under N₂ at −50° C. The reactionmixture was stirred at the same temperature and allowed to warm to −40°C. over 1.5 h. The reaction mixture was quenched with saturated aqueousNH₄Cl solution and allowed to warm up to room temperature over 1 h. Thereaction mixture was acidified with 1 N aqueous HCl, diluted with EtOAc,washed with brine and dried over Na₂SO₄. The solvent was removed underreduced pressure to give a crude residue.

The above crude residue was stirred in a mixture of H₂SO₄ (25 mL) inMeOH (250 mL) at reflux for 5 h. It was then cooled to room temperatureand concentrated under reduced pressure. The obtained residue wasdiluted with EtOAc and brine. The organic layer was separated, driedwith Na₂SO₄, concentrated under reduced pressure and purified by silicagel flash chromatography (0 to 50% EtOAc in hexanes) to give methyl4-bromo-5-fluoro-1H-indole-7-carboxylate. MS: (ES) m/z calculated forC₁₀H₈BrFNO₂ [M+H]⁺ 271.9, found 271.9.

Step b: To a suspension of methyl4-bromo-5-fluoro-1H-indole-7-carboxylate (0.900 g, 3.3 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.51 g,5.94 mmol), and KOAc (1.62 g, 16.5 mmol) in DMSO (19 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (400 mg, 0.49 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 115° C. for1.5 h. The reaction mixture was diluted with EtOAc, filtered throughCelite, washed with brine and dried over Na₂SO₄. The solvent was removedunder reduced pressure and the residue was purified by silica gel flashchromatography (0 to 100% CH₂Cl₂/hexanes) to give methyl5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate.MS: (ES) m/z calculated for C₁₆H₂₀BFNO₄ [M+H]⁺ 320.1, found 320.1.

Step c: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(1.00 g, 2.31 mmol), methyl5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate(740 mg, 2.31 mmol) and K₂CO₃ (1.28 g, 9.24 mmol) in p-dioxane (14 mL)and water (2.5 mL) was added Pd(dppf)Cl₂ complex with dichloromethane(400 mg, 0.49 mmol). The reaction mixture was degassed (N₂) for 2 minand stirred under N₂ at 100° C. for 2.5 h. The reaction mixture wasdiluted with EtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (0 to 70% EtOAc in hexanes)to give tert-butyl2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxycarbonyl-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₃₁H₃₆FN₄O₄[M+H]⁺ 547.2, found 547.2.

Step d: The above tert-butyl2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxycarbonyl-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(1.00 g, 1.83 mmol) was dissolved in THF (35 mL) and charged with asolution of LiAlH₄ in ether (1 M, 2.7 mL) at 0° C. The resulting mixturewas stirred at 0° C. for 40 min. It was then quenched with water,diluted with IPA/CHCl₃ (1:3), washed with brine and dried over Na₂SO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (0 to 90% EtOAc in hexanes)to give tert-butyl2-(2,6-diethylphenyl)-3-[5-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₆FN₄O₃[M+H]⁺ 519.2, found 519.2.

The above tert-butyl2-(2,6-diethylphenyl)-3-(5-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(650 mg, 1.25 mmol) was dissolved in dichloromethane (13 mL) and chargedwith HCl in dioxane (4N, 35 mL). The resulting mixture was stirred atroom temperature for 1.5 h. After the reaction was complete, the solventwas evaporated in vacuo to give[4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanolhydrochloride. MS: (ES) m/z calculated for C₂₅H₂₈FN₄O [M+H]⁺ 419.2,found 419.2.

Step e: Triethylamine (1.50 mL, 10.7 mmol) was added to a suspension of[4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanolhydrochloride (600 mg, 1.32 mmol) and2-chloro-5-(trifluoromethyl)pyrimidine (350 mg, 1.9 mmol) in MeCN (70mL). The resulting mixture was stirred at 80° C. for 30 min. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 90% EtOAc in hexanes) to afford[4-[2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanol.¹H NMR (400 MHz, CDCl₃) δ 9.05 (br s, 1H), 8.47 (br s, 2H), 7.27 (m,1H), 7.16 (m, 2H), 6.86 (d, J=7.26 Hz, 1H), 6.56 (d, J=10.0 Hz, 1H),6.37 (t, J=2.6 Hz, 1H), 4.88 (m, 3H), 4.68 (d, J=16.4 Hz, 1H), 4.43 (m,1H), 4.29 (m, 1H), 3.04 (t, J=6.0 Hz, 2H), 2.38-2.58 (m, 3H), 2.17(sextet, J=7.3 Hz, 1H), 1.94 (sextet, J=7.3 Hz, 1H), 1.21 (t, J=7.4 Hz,3H), 0.75 (t, J=7.4 Hz, 3H). MS: (ES) m/z calculated for C₃₀H₂₉F₄N₆O[M+H]⁺ 565.2, found 565.2.

Example 28 Synthesis of[4-[5-(5-cyclopropylpyrimidin-2-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanol

A mixture of[4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanolhydrochloride (35 mg, 0.077 mmol) (intermediate from Example 2), NEt₃(0.12 mL, 0.86 mmol), 2-chloro-5-cyclopropyl-pyrimidine (40 mg, 0.025mmol) and Li₂CO₃ (120 mg, 1.62 mmol) in DMSO (1.5 mL) was stirred at120° C. for 6 h. After cooling to room temperature, the reaction mixturewas diluted with EtOAc, washed with aqueous NaHCO₃ and dried overNa₂SO₄. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (0 to 85% EtOAc inhexanes) to afford[4-[5-(5-cyclopropylpyrimidin-2-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanol.¹H NMR (400 MHz, CDCl₃) δ 8.96 (br s, 1H), 8.10 (s, 2H), 7.22 (t, J=2.8Hz, 1H), 7.14 (m, 2H), 6.86 (dd, J=1.2, 7.2 Hz, 1H), 6.49 (d, J=10.0 Hz,1H), 6.37 (t, J=2.6, 1H), 4.68-4.76 (m, 2H), 4.58-4.70 (m, 2H), 4.44 (m,1H), 4.12 (quint, J=6.4 Hz, 1H), 3.10 (br s, 1H), 3.02 (d, J=5.8 Hz,2H), 2.51 (sextet, J=7.5 Hz, 1H), 2.44 (sextet, J=7.6 Hz, 1H), 2.08 (m,1H), 1.95 (sextet, J=7.5 Hz, 1H), 1.68 (m, 1H), 1.21 (t, J=7.6 Hz, 3H),0.87 (m, 2H), 0.76 (t, J=7.5 Hz, 3H), 0.55 (m, 2H). MS: (ES) m/zcalculated for C₃₂H₃₄FN₆O [M+H]⁺ 537.2, found 537.2.

Example 29 Synthesis of[4-[2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-6-fluoro-1H-indol-7-yl]methanol

Step a: A mixture of 4-bromo-2-fluoro-6-nitrotoluene (5.50 g, 23.5mmol), KMnO₄ (40 g, 253 mmol) in pyridine (100 mL) and water (75 mL) wasstirred at 100° C. for 5 h. It was then cooled to room temperature,diluted with MeOH and filtered over Celite. The filtrate was acidifiedwith 1 M aqueous HCl. The mixture was extracted with EtOAc. The organiclayer was separated, dried over Na₂SO₄, concentrated under reducedpressure and purified by silica gel flash chromatography (0 to 100%EtOAc in DCM) to afford 4-bromo-2-fluoro-6-nitro-benzoic acid. ¹H NMR(400 MHz, CDCl₃) δ 8.89 (br s, 1H), 8.14 (t, J=1.6 Hz, 1H), 7.70 (dd,J=1.6, 8.0 Hz, 1H).

Step b: Vinylmagnesium bromide solution in THF (1 M, 32.4 mL, 32.4 mmol)was added to a solution of 4-bromo-2-fluoro-6-nitro-benzoic acid (1.43g, 5.4 mmol) in anhydrous THF (30 mL) under N₂ at −40° C. The reactionmixture was stirred at the same temperature and allowed to warm to −30°C. over 1 h. The reaction mixture was quenched with saturated aqueousNH₄Cl solution and allowed to warm up to room temperature over 1 h. Thereaction mixture was acidified with 1 N aqueous HCl, diluted with EtOAc,washed with brine and dried over Na₂SO₄. The solvent was removed underreduced pressure to give a crude acid residue.

The above acid was stirred in a mixture of conc. H₂SO₄ (5 mL) in MeOH(100 mL) at reflux for 6 h. The mixture was then cooled to roomtemperature and concentrated under reduced pressure. The obtainedresidue was diluted with EtOAc and basified with saturated aqueousNaHCO₃. The organic layer was separated, washed with brine, dried withNa₂SO₄, concentrated under reduced pressure and purified by silica gelflash chromatography (0 to 100% DCM/hexanes) to afford methyl4-bromo-6-fluoro-1H-indole-7-carboxylate. MS: (ES) m/z calculated forC₁₀H₈BrFNO₂ [M+H]⁺ 271.9, found 271.9.

Step c: To a suspension of methyl4-bromo-6-fluoro-1H-indole-7-carboxylate (380 mg, 1.4 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (461 mg, 1.8mmol) and KOAc (412 mg, 4.2 mmol) in dioxane (9 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (160 mg, 0.20 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 115° C. for1.5 h. The reaction mixture was diluted with EtOAc and filtered overCelite. The filtrate was concentrated under reduced pressure and theobtained residue was purified by silica gel flash chromatography (0 to100% CH₂Cl₂/hexanes, followed by 0 to 20% EtOAc in DCM) to give methyl6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate.MS: (ES) m/z calculated for C₁₆H₂₀BFNO₄ [M+H]⁺ 320.1, found 320.1.

Step d: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(295 mg, 0.68 mmol), methyl6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate(220 mg, 0.68 mmol), K₂CO₃ (400 mg, 2.9 mmol) in p-dioxane (7 mL) andwater (1.4 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (160mg, 0.20 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 2.5 h. The reaction mixture was dilutedwith EtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel flash chromatography (0 to 50% EtOAc in hexanes) to givetert-butyl2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxycarbonyl-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₃₁H₃₆FN₄O₄[M+H]⁺ 547.2, found 547.2.

Step e: The above tert-butyl2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxycarbonyl-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(300 mg, 0.54 mmol) was dissolved in THF (4 mL) and charged with LiAlH₄in ether (2 M, 0.548 mL, 1.1 mmol) at 0° C. The resulting mixture wasstirred at 0° C. for 10 min. It was then quenched with methanol anddiluted with EtOAc and brine. The organic layer was separated, driedover Na₂SO₄, concentrated under reduced pressure and purified by silicagel flash chromatography (0 to 100% EtOAc in hexanes) to give tert-butyl2-(2,6-diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₆FN₄O₃[M+H]⁺ 519.2, found 519.2. Theabove tert-butyl2-(2,6-diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(195 mg, 0.37 mmol) was dissolved in dichloromethane (1.3 mL) andcharged with HCl in dioxane (4N, 5 mL). The resulting mixture wasstirred at room temperature for 1.5 h. The solvent was evaporated invacuo to give[4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-6-fluoro-1H-indol-7-yl]methanolhydrochloride. MS: (ES) m/z calculated for C₂₅H₂₈FN₄O [M+H]⁺ 419.2,found 419.2.

Step f: Triethylamine (0.12 mL, 0.85 mmol) was added to a suspension of[4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-6-fluoro-1H-indol-7-yl]methanolhydrochloride (25 mg, 0.055 mmol) and2-chloro-5-(trifluoromethyl)pyrimidine (60 mg, 0.32 mmol) in MeCN (1.5mL). The resulting mixture was stirred at 85° C. for 30 min. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 85% EtOAc in hexanes) to afford[4-[2-(2,6-diethylphenyl)-6-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanol.¹H NMR (400 MHz, CDCl₃) δ 9.17 (br s, 1H), 8.48 (br s, 2H), 7.27 (m,1H), 7.22 (t, J=7.6 Hz, 1H), 7.04 (d, J=7.6 Hz, 2H), 6.44 (t, J=2.6 Hz,1H), 6.37 (d, J=11.6 Hz, 1H), 5.05 (d, J=5.6 Hz, 2H), 4.84 (br s, 2H),4.36 (br s, 2H), 3.03 (t, J=5.8 Hz, 2H), 2.10-2.40 (m, 4H), 2.15 (t,J=5.4 Hz, 1H), 1.01 (m, 6H). MS: (ES) m/z calculated for C₃₀H₂₉F₄N₆O[M+H]⁺ 565.2, found 565.2.

Example 30 Synthesis of2-[2-[2-(2,6-diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidin-5-yl]propan-2-ol

Step a: A mixture of[4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-6-fluoro-1H-indol-7-yl]methanolhydrochloride (38 mg, 0.083 mmol) (intermediate from Example 10), methyl2-chloropyrimidine-5-carboxylate (70 mg, 0.40 mmol) and NEt₃ (0.12 mL,0.85 mmol) in CH₃CN (2 mL) was stirred at 80° C. for 20 min. It was thencooled to room temperature, diluted with EtOAc, washed with aqueousNaHCO₃ and dried over Na₂SO₄. The solvent was removed under reducedpressure and the residue was purified by silica gel flash chromatography(0 to 80% EtOAc in hexanes) to afford methyl2-[2-(2,6-diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylate.MS: (ES) m/z calculated for C₃₁H₃₂FN₆O₃[M+H]⁺ 555.2, found 555.2.

Step b: To a solution of methyl2-[2-(2,6-diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylate(38 mg, 0.068 mmol) in THF (2 mL) was added CH₃Li (0.35 mL, 0.56 mmol,1.6 M in ether) at 0° C. The obtained mixture was stirred at the sametemperature for 20 min, quenched with saturated NH₄Cl and extracted withEtOAc. The organic layer was separated, washed with aqueous NaHCO₃,dried over Na₂SO₄, concentrated under reduced pressure and purified bysilica gel flash chromatography (0 to 100% EtOAc in hexanes) to afford2-[2-[2-(2,6-diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidin-5-yl]propan-2-ol.¹H NMR (400 MHz, CDCl₃) δ 8.91 (br s, 1H), 8.20 (br s, 2H), 6.95-7.10(m, 2H), 6.80 (br s, 2H), 6.23 (br s, 1H), 6.14 (d, J=11.2 Hz, 1H), 4.67(s, 2H), 4.54 (s, 2H), 4.09 (br s, 1H), 3.91 (m, 1H), 2.80 (br s, 2H),2.71 (br s, 1H), 1.90-2.20 (br m, 4H), 1.83 (br s, 6H), 1.61 (br s, 6H).MS: (ES) m/z calculated for C₃₂H₃₆FN₆O₂[M+H]⁺ 555.3, found 555.3.

Example 31 Synthesis of3-(7-chloro-6-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: Tert-butyl nitrite (5.03 mL, 42.4 mmol) was added dropwise to asolution of 4-bromo-2-fluoro-6-nitroaniline (5.00 g, 21.2 mmol) andCuCl₂ (8.55 g, 63.6 mmol) in CH₃CN (100 mL) at room temperature. Thereaction mixture was stirred at room temperature for 1 h and quenchedwith water. The mixture was diluted with EtOAc, washed with brine anddried over Na₂SO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (0 to 30%EtOAc in hexanes) to give 5-bromo-2-chloro-1-fluoro-3-nitro-benzene.

Step b: Vinylmagnesium bromide solution in THF (1 M, 56 mL, 56 mmol) wasadded to a solution of 5-bromo-2-chloro-1-fluoro-3-nitro-benzene (4.10g, 16 mmol) in anhydrous THF (100 mL) under N₂ at −40° C. The reactionmixture was allowed to warm up to −30° C. over 1 h. The reaction mixturewas quenched with saturated aqueous NH₄Cl solution and allowed to warmup to room temperature over 1 h. The reaction mixture was diluted withEtOAc, washed with brine and dried over Na₂SO₄. The solvent was removedunder reduced pressure and the residue was purified by silica gel flashchromatography (0 to 100% DCM/hexanes) to give4-bromo-7-chloro-6-fluoro-1H-indole. ¹H NMR (400 MHz, CDCl₃) δ 7.29 (t,J=2.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.60 (t, J=2.6 Hz, 1H).

Step c: To a suspension of 4-bromo-7-chloro-6-fluoro-1H-indole (800 mg,3.2 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(981 mg, 3.86 mmol), and KOAc (942 mg, 9.6 mmol) in dioxane (15 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (300 mg, 0.37 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for2 h. The reaction mixture was cooled to room temperature, diluted withEtOAc and filtered through Celite. The solvent was removed under reducedpressure and the residue was purified by silica gel flash chromatography(0 to 100% DCM/hexanes) to give7-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₄H₁₇BClFNO₂ [M+H]⁺ 296.1, found 296.1.

Step d: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(293 mg, 0.67 mmol),7-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(200 mg, 0.67 mmol) and K₂CO₃ (370 mg, 2.67 mmol) in p-dioxane (6 mL)and water (0.7 mL) was added Pd(dppf)Cl₂ complex with dichloromethane(150 mg, 0.18 mmol). The reaction mixture was degassed (N₂) for 2 minand stirred under N₂ at 100° C. for 1.5 h. The reaction mixture wascooled to room temperature, diluted with EtOAc, washed with aqueousNaHCO₃ and dried over Na₂SO₄. The solvent was removed under reducedpressure and the residue was purified by silica gel flash chromatography(0 to 50% EtOAc in hexanes) to give tert-butyl3-(7-chloro-6-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₃ClFN₄O₂[M+H]⁺ 523.2, found 523.2.

The above tert-butyl3-(7-chloro-6-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(226 mg, 0.56 mmol) was dissolved in dichloromethane (2 mL) and chargedwith HCl in dioxane (4N, 7 mL). The resulting mixture was stirred atroom temperature for 1 h. The solvent was evaporated in vacuo to give3-(7-chloro-6-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₄H₂₅ClFN₄ [M+H]⁺ 423.2,found 423.2.

Step e: Triethylamine (0.49 mL, 3.48 mmol) was added to a suspension of3-(7-chloro-6-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (400 mg, 0.87 mmol) and2-chloro-5-(trifluoromethyl)pyrimidine (192 mg, 1.05 mmol) in MeCN (9mL). The resulting mixture was stirred at 80° C. for 1 h. After coolingto room temperature, the reaction mixture was diluted with EtOAc, washedwith aqueous NaHCO₃ and dried over Na₂SO₄. The solvent was removed underreduced pressure and the residue was purified by silica gel flashchromatography (0 to 45% EtOAc in hexanes) to afford3-(7-chloro-6-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.54 (br s, 1H), 8.49 (br s, 2H), 7.30 (d,J=2.8 Hz, 1H), 7.26 (d, J=7.0 Hz, 1H), 7.06 (d, J=7.2 Hz, 2H), 6.50 (m,2H), 4.84 (br s, 2H), 4.36 (t, J=5.6 Hz, 2H), 3.04 (t, J=5.6 Hz, 2H),2.25 (m, 4H), 1.01 (br s, 6H). MS: (ES) m/z calculated forC₂₉H₂₆ClF₄N₆[M+H]⁺ 569.2, found 569.2.

Example 32 Synthesis of2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: A mixture of 4-bromo-5-fluoro-2-nitrophenol (4.70 g, 19.9 mmol),CH₃I (3.72 mL, 59.7 mmol) and K₂CO₃ (8.25 g, 59.7 mmol) in DMF (60 mL)was stirred at 45° C. for 45 min. It was then cooled to roomtemperature, diluted with ether, washed with brine and dried overNa₂SO₄. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (0 to 100%CH₂Cl₂/hexanes) to give 1-bromo-2-fluoro-4-methoxy-5-nitro-benzene. ¹HNMR (400 MHz, CDCl₃) δ 8.16 (d, J=7.6 Hz, 1H), 6.88 (d, J=9.6 Hz, 1H),3.96 (s, 3H).

Step b: Vinylmagnesium bromide solution in THF (1 M, 60 mL, 60 mmol) wasadded to a solution of 1-bromo-2-fluoro-4-methoxy-5-nitro-benzene (4.55g, 18.2 mmol) in anhydrous THF (180 mL) under N₂ at −50° C. The reactionmixture was stirred at the same temperature and allowed to warm to −30°C. over 3 h. The reaction mixture was quenched with saturated aqueousNH₄Cl solution and allowed to warm up to room temperature over 1 h. Thereaction mixture was diluted with EtOAc, washed with brine and driedover Na₂SO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (0 to 100% DCMin hexanes) to give 4-bromo-5-fluoro-7-methoxy-1H-indole. MS: (ES) m/zcalculated for C₉H₈BrFNO [M+H]⁺ 243.9, found 243.9.

Step c: To a suspension of 4-bromo-5-fluoro-7-methoxy-1H-indole (0.200g, 0.82 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.271 g,1.06 mmol) and KOAc (0.241 g, 2.46 mmol) in dioxane (5 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (0.130 g, 0.16 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for10 h. The reaction mixture was cooled to room temperature, diluted withEtOAc and filtered through Celite. The solvent was removed under reducedpressure and the residue was purified by silica gel flash chromatography(0 to 100% DCM in hexanes) to give5-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₅H₂₀BFNO₃ [M+H]⁺ 292.1, found 292.1.

Step d: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(0.060 g, 0.137 mmol),5-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(0.040 g, 0.137 mmol), K₂CO₃ (0.076 g, 0.50 mmol) in p-dioxane (2 mL)and water (0.3 mL) was added Pd(dppf)Cl₂ complex with dichloromethane(0.070 g, 0.086 mmol). The reaction mixture was degassed (N₂) for 2 minand stirred under N₂ at 100° C. for 2 h. The reaction mixture was cooledto room temperature, diluted with EtOAc, washed with aqueous NaHCO₃ anddried over Na₂SO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (0 to 100%EtOAc in hexanes) to give tert-butyl2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₆FN₄O₃[M+H]⁺ 519.2, found 519.2. Theabove tert-butyl2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(0.019 g, 0.036 mmol) was dissolved in dichloromethane (1 mL) andcharged with HCl in dioxane (4N, 2 mL). The resulting mixture wasstirred at room temperature for 1 h. The solvent was evaporated in vacuoto give2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₈FN₄O [M+H]⁺ 419.2,found 419.2.

Step e: Triethylamine (0.12 mL, 0.86 mmol) was added to a suspension of2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (0.019 g, 0.034 mmol) and2-chloro-5-(trifluoromethyl)pyrimidine (0.030 g, 0.16 mmol) in MeCN (1.5mL). The resulting mixture was stirred at 80° C. for 0.5 h. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 50% EtOAc in hexanes) to afford2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.46 (two br s, 3H), 7.12-7.22 (m, 3H), 6.89(d, J=6.0 Hz, 1H), 6.33 (t, J=2.8 Hz, 1H), 6.28 (d, J=11.6 Hz, 1H), 4.90(d, J=16 Hz, 1H), 4.70 (d, J=16 Hz, 1H), 4.43 (quint, J=6.2 Hz, 1H),4.29 (quint, J=6.3 Hz, 1H), 3.87 (s, 3H), 3.04 (t, J=6.0 Hz, 2H), 2.51(sextet, J=7.4 Hz, 1H), 2.43 (sextet, J=7.6 Hz, 1H), 2.17 (sextet, J=7.5Hz, 1H), 1.97 (sextet, J=7.5 Hz, 1H), 1.21 (t, J=7.6 Hz, 3H), 0.75 (t,J=7.6 Hz, 3H). MS: (ES) m/z calculated for C₃₀H₂₉ClF₄N₆O [M+H]⁺ 565.2,found 565.2.

Example 33 Synthesis2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-H-indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Triethylamine (0.12 mL, 0.86 mmol) was added to a suspension of2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (13 mg, 0.023 mmol) and2,3-difluoro-5-(trifluoromethyl)pyridine (50 mg, 0.29 mmol) in MeCN (1.5mL). The resulting mixture was stirred at 80° C. for 0.5 h. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 45% EtOAc in hexanes) to afford2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.44 (br s, 1H), 8.17 (d, J=0.8 Hz, 1H), 7.38(dd, J=13.2 Hz, 1.6, 1H), 7.12-7.22 (m, 3H), 6.88 (d, J=7.6 Hz, 1H),6.34 (t, J=2.6 Hz, 1H), 6.27 (d, J=11.6 Hz, 1H), 4.73 (d, J=16 Hz, 1H),4.46 (d, J=16 Hz, 1H), 4.06 (m, 2H), 3.87 (s, 3H), 3.11 (t, J=5.6 Hz,2H), 2.52 (sextet, J=7.6 Hz, 1H), 2.43 (sextet, J=7.5 Hz, 1H), 2.17(sextet, J=7.6 Hz, 1H), 1.96 (sextet, J=7.5 Hz, 1H), 1.24 (t, J=7.6 Hz,3H), 0.75 (t, J=7.6 Hz, 3H). MS: (ES) m/z calculated for C₃₁H₂₉F₅N₅O[M+H]⁺ 582.2, found 582.2.

Example 34 Synthesis of3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (500 mg, 1.2 mmol),7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(350 mg, 1.26 mmol), and K₂CO₃ (300 mg, 2.2 mmol) in p-dioxane (6 mL)and water (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (200mg, 0.24 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 2 h. The reaction mixture was dilutedwith EtOAc, filtered through Celite, washed with brine and dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (5 to 30% EtOAc inhexanes) to give tert-butyl3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. MS: (ES) m/z calculated for C₂₈H₃₃ClN₅O₂[M+H]⁺ 506.2,found 506.2. The above tert-butyl3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylatewas dissolved in dichloromethane (5 mL) and charged with HCl in dioxane(4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the reaction was complete, the solvent was evaporated in vacuoto give3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₃H₂₅ClN₅ [M+H]⁺ 406.2,found 406.2.

Step b: N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to asuspension of3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.11 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine(20 mg, 0.11 mmol), and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (10 mL) undermagnetic stirring. The resulting mixture was stirred at 65° C. for 1 h.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by Preparative TLC(45% EtOAc in hexanes) followed by trituration in MeOH to afford3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 10.43 (s, 1H), 8.58 (s, 2H), 8.15 (s, 1H),7.24-7.28 (m, 2H), 7.11 (d, J=7.7 Hz, 2H), 6.69 (d, J=7.7 Hz, 1H), 4.95(s, 2H), 4.44 (t, J=6.0 Hz, 2H), 3.12 (t, J=6.0 Hz, 2H), 2.21-2.39 (m,4H), 1.02-1.09 (m, 6H). MS: (ES) m/z calculated C₂₈H₂₆ClF₃N₇[M+H]⁺552.2, found 552.2.

Example 35 Synthesis of3-(7-chloro-1H-indazol-4-yl)-5-(5-cyclopropylpyrimidin-2-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.11 mmol), 2-chloro-5-cyclopropylpyrimidine (40mg, 0.26 mmol), and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (5 mL) undermagnetic stirring. The resulting mixture was stirred at 120° C. for 2 h.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by Preparative TLC(45% EtOAc in hexanes) to afford3-(7-chloro-1H-indazol-4-yl)-5-(5-cyclopropylpyrimidin-2-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.10-8.17 (m, 2H), 8.13 (s,1H), 7.12-7.21 (m, 2H), 7.04 (d, J=7.7 Hz, 2H), 6.61 (d, J=7.7 Hz, 1H),4.79 (s, 2H), 4.28 (t, J=5.9 Hz, 2H), 3.02 (t, J=5.9 Hz, 2H), 2.10-2.36(m, 4H), 1.71 (m, 1H), 1.00 (t, J=4.0 Hz, 6H), 0.88 (m, 2H), 0.59 (m,2H). MS: (ES) m/z calculated C₃₀H₃₁ClN₇ [M+H]⁺ 524.2, found 524.2.

Example 36 Synthesis of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: Lithium diisopropylamine solution in THF (1 M, 25 mL, 25 mmol)was added slowly to a solution of 5-bromo-1,3-difluoro-2-methoxybenzene(4.5 g, 20.2 mmol) in anhydrous THF (50 mL) under N₂ and vigorouslystirred at −78° C. The reaction mixture was stirred at −60° C. for 1 h,followed by rapid addition of DMF (5 mL). The reaction mixture wasstirred at the same temperature and allowed to warm to −50° C. over 1 h.The reaction was poured into a mixture of ice (200 g), concentratedhydrochloric acid (20 mL) and MTBE (100 mL) and the mixture was stirredand allowed to warm up to room temperature over 2 h. The oranic layerwas separated, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure to give6-bromo-2,4-difluoro-3-methoxybenzaldehyde. MS: (ES) m/z calculated forC₈H₆BrF₂O₂[M+H]⁺ 250.9, found 250.9.

To the solution of the above 6-bromo-2,4-difluoro-3-methoxybenzaldehyde(1.5 g, 6.0 mmol) in DME (7 mL) was added hydrazine monohydrate (7 mL).The resulting mixture was stirred at 90° C. for 3 h. After cooling toroom temperature, the reaction mixture was diluted with EtOAc, washedwith brine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by silica gel flash chromatography(5 to 40% EtOAc in hexanes) to afford4-bromo-6-fluoro-7-methoxy-1H-indazole. MS: (ES) m/z calculated forC₈H₇BrFN₂O [M+H]⁺ 244.9, found 244.9.

Step b: To a suspension 4-bromo-6-fluoro-7-methoxy-1H-indazole (500 mg,2.04 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(1.0 g, 3.9 mmol), and KOAc (1 g, 10.2 mmol) in DMSO (12 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (500 mg, 0.61 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 120° C. for1.5 h. The reaction mixture was diluted with EtOAc, washed with brineand dried over MgSO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (5 to 25%EtOAc in hexanes) to give6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.MS: (ES) m/z calculated for C₁₄H₁₉BFN₂O₃ [M+H]⁺ 293.1, found 293.2.

Step c: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(500 mg, 1.2 mmol),6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(400 mg, 1.37 mmol), K₂CO₃ (600 mg, 4.4 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (200 mg,0.24 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give tert-butyl2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₅FN₅O₃[M+H]⁺ 520.3, found 520.3. Theabove tert-butyl2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate was dissolved in dichloromethane (5 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. After the reaction was complete, the solventwas evaporated in vacuo to give2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₄H₂₇FN₅O [M+H]⁺ 420.2,found 420.2.

Step d: N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to asuspension of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.11 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine(20 mg, 0.11 mmol), and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (10 mL) undermagnetic stirring. The resulting mixture was stirred at 65° C. for 1 h.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by Preparative TLC(50% EtOAc in hexanes) followed by trituration in MeOH to afford2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 10.27 (s, 1H), 8.51 (s, 2H), 7.96 (d, J=0.6Hz, 1H), 7.26 (m, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.43-6.51 (m, 1H), 4.88(s, 2H), 4.37 (t, J=5.9 Hz, 2H), 4.13 (dd, J=0.6, 3.0 Hz, 3H), 3.04 (t,J=5.9 Hz, 2H), 2.14-2.33 (m, 4H), 1.02 (t, J=7.5 Hz, 6H). MS: (ES) m/zcalculated C₂₉H₂₈F₄N₇O [M+H]⁺ 566.2, found 566.2.

Example 37 Synthesis of2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (30 mg, 0.07 mmol),2,3-difluoro-5-(trifluoromethyl)pyridine (15 mg, 0.08 mmol), and Li₂CO₃(20 mg, 0.27 mmol) in DMSO (10 mL) under magnetic stirring. Theresulting mixture was stirred at 65° C. for 2 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withbrine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by Preparative TLC (40% EtOAc inhexanes) followed by trituration in MeOH to afford2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 10.30 (s, 1H), 8.22 (dd, J=1.2, 2.3 Hz, 1H),8.00 (s, 1H), 7.41 (dd, J=2.0, 13.2 Hz, 1H), 7.18-7.30 (m, 1H), 7.07 (d,J=7.7 Hz, 2H), 6.46 (d, J=13.1 Hz, 1H), 4.67 (s, 2H), 4.13 (s, 3H), 4.08(t, J=5.9 Hz, 2H), 3.10 (t, J=5.9 Hz, 2H), 2.13-2.36 (m, 4H), 1.02 (t,J=8.0 Hz, 6H). MS: (ES) m/z calculated C₃₀H₂₈F₅N₆O [M+H]⁺ 583.2, found583.2.

Example 38 Synthesis of3-(7-methoxy-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of 4-bromo-7-methoxy-1H-indazole (500 mg, 2.2mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.2g, 2.7 mmol), and KOAc (690 mg, 7.0 mmol) in DMSO (8 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (400 mg, 0.49 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 120° C. for2 h. The reaction mixture was diluted with EtOAc and filtered throughCelite. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (5 to 40% EtOAc inhexanes) to give7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.MS: (ES) m/z calculated for C₁₄H₂₀BN₂O₃[M+H]⁺ 275.2, found 275.2.

Step b: To a suspension of tert-butyl3-bromo-2-(2,5-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(250 mg, 0.56 mmol),7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(310 mg, 1.1 mmol), K₂CO₃ (260 mg, 1.9 mmol) in p-dioxane (6 mL) andwater (1.5 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (200mg, 0.25 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 3 h. The reaction mixture was dilutedwith EtOAc, and filtered through Celite. The solvent was removed underreduced pressure and the residue was purified by silica gel flashchromatography (10 to 80% MTBE in hexane) to give tert-butyl3-(7-methoxy-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5-(4H)-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₆N₅O₃ [M+H]⁺ 502.3, found 502.3.

The above tert-butyl3-(7-methoxy-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5-(4H)-carboxylatewas dissolved in dichloromethane (15 mL) and treated with HCl in dioxane(4N, 3 mL). The resulting mixture was stirred at room temperature for 1h. After the reaction was complete, the solvent was evaporated in vacuoto give3-(7-methoxy-1H-indazol-4-yl)-2(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₄H₂₈N₅O [M+H]⁺ 402.2, found402.2.

Step c: N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) was added to asuspension of3-(7-methoxy-1H-indazol-4-yl)-2(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (52 mg, 0.11 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine(25 mg, 0.14 mmol) and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (1 mL) undermagnetic stirring. The resulting mixture was stirred at room temperaturefor 9 h. The solvent was removed in vacuo and the residue was purifiedby silica gel flash chromatography (4 to 40% EtOAc in hexanes) to obtain3-(7-methoxy-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, d₆-DMSO) δ 8.70 (br s, 2H), 7.95 (s, 1H), 7.25 (t,J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 2H), 6.69 (d, J=8.0 Hz, 1H), 6.49 (d,J=8.0 Hz, 1H), 4.79 (s, 2H), 4.31 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 2.89(t, J=5.6 Hz, 2H), 2.0-2.3 (m, 4H), 0.8-1.0 (m, 6H). MS: (ES) m/zcalculated for C₂₉H₂₉F₃N₇O [M+H]⁺ 548.2, found 548.2.

Example 39 Synthesis of2-(2,6-diethylphenyl)-3-(6,7-difluoro-1H-indol-4-yl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: Vinylmagnesium bromide solution in THF (1 M, 65.8 mL, 65.8 mmol)was added to a solution of 5-bromo-1,2-difluoro-3-nitro-benzene (4.90 g,20.58 mmol) in anhydrous THF (70 mL) under N₂ at −55° C. The reactionmixture was stirred at the same temperature and allowed to warm to −45°C. over 1.5 h. The reaction mixture was quenched with saturated aqueousNH₄Cl solution and allowed to warm up to room temperature over 1 h. Thereaction mixture was diluted with EtOAc, washed with brine and driedover Na₂SO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (0 to 30% EtOAcin hexanes) to give 4-bromo-6,7-difluoro-1H-indole. MS: (ES) m/zcalculated for C₈H₅BrF₂N [M+H]⁺ 231.9, found 231.9.

Step b: To a suspension of 4-bromo-6,7-difluoro-1H-indole (0.500 g, 2.15mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.657 g, 2.6 mmol) and KOAc (0.633 g, 6.45 mmol) in dioxane (12 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (0.200 g, 0.24 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for1.5 h. The reaction mixture was diluted with EtOAc and filtered throughCelite. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (0 to 80% DCM/hexanes)to give6,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₄H₁₇BF₂NO₂ [M+H]⁺ 280.1, found 280.1.

Step c: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(0.356 g, 0.82 mmol),6,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(0.230 g, 0.82 mmol), K₂CO₃ (0.350 g, 2.53 mmol) in p-dioxane (10 mL)and water (1.2 mL) was added Pd(dppf)Cl₂ complex with dichloromethane(0.150 g, 0.18 mmol). The reaction mixture was degassed (N₂) for 2 minand stirred under N₂ at 100° C. for 2 h. The reaction mixture wasdiluted with EtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (0 to 60% EtOAc in hexanes)to give tert-butyl2-(2,6-diethylphenyl)-3-(6,7-difluoro-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₃F₂N₄O₂[M+H]⁺ 507.2, found 507.2.

The above tert-butyl2-(2,6-diethylphenyl)-3-(6,7-difluoro-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(0.255 g, 0.60 mmol) was dissolved in dichloromethane (1.5 mL) andcharged with HCl in dioxane (4N, 4 mL). The resulting mixture wasstirred at room temperature for 1 h. The solvent was evaporated in vacuoto give2-(2,6-diethylphenyl)-3-(6,7-difluoro-1H-indol-4-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₇FN₄O [M+H]⁺ 407.2,found 407.2.

Step d: Triethylamine (0.12 mL, 0.86 mmol) was added to a suspension of2-(2,6-diethylphenyl)-3-(6,7-difluoro-1H-indol-4-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (0.025 g, 0.056 mmol) and2-chloro-5-(trifluoromethyl)pyrimidine (60 mg, 0.33 mmol) in MeCN (1.5mL). The resulting mixture was stirred at 80° C. for 45 min. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 45% EtOAc in hexanes) to afford2-(2,6-diethylphenyl)-3-(6,7-difluoro-1H-indol-4-yl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.60 (br s, 1H), 8.50 (br s, 2H), 7.20-7.25(m, 2H), 7.06 (d, J=7.2 Hz, 2H), 6.47 (m, 2H), 4.83 (br s, 2H), 4.36 (t,J=5.4 Hz, 2H), 3.04 (t, J=5.4 Hz, 2H), 2.02-2.40 (br s, 4H), 1.00 (br s,6H). MS: (ES) m/z calculated for C₂₉H₂₆F₅N₆ [M+H]⁺ 553.2, found 553.2.

Example 40 Synthesis of3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: Vinylmagnesium bromide solution in THF (1 M, 37.7 mL, 37.7 mmol)was added to a solution of 1-bromo-4-chloro-2-fluoro-5-nitro-benzene(3.00 g, 11.8 mmol) in anhydrous THF (40 mL) under N₂ at −60° C. Thereaction mixture was stirred at the same temperature and allowed to warmto −40° C. over 1.5 h. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution and allowed to warm up to room temperature over 1h. The reaction mixture was diluted with ether, washed with brine anddried over Na₂SO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (0 to 40%EtOAc in hexanes) to give 4-bromo-7-chloro-5-fluoro-1H-indole. MS: (ES)m/z calculated for C₈H₅BrClFN [M+H]⁺ 247.9, found 247.9.

Step b: To a suspension of 4-bromo-7-chloro-5-fluoro-1H-indole (300 mg,1.2 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(1.44 g, 0.368 mmol), and KOAc (356 mg, 3.6 mmol) in dioxane (8 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (120 mg, 0.15 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C.overnight. The reaction mixture was cooled to room temperature, dilutedwith EtOAc and filtered through Celite. The solvent was removed underreduced pressure and the residue was purified by silica gel flashchromatography (0 to 100% DCM in hexanes) to give7-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₄H₁₇BClFNO₂ [M+H]⁺ 296.1, found 296.1.

Step c: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(169 mg, 0.39 mmol),7-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(115 mg, 0.39 mmol), K₂CO₃ (230 mg, 1.66 mmol) in p-dioxane (6 mL) andwater (0.7 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (120mg, 0.15 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 2 h. The reaction mixture was cooled toroom temperature, diluted with EtOAc, washed with aqueous NaHCO₃ anddried over Na₂SO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (0 to 50%EtOAc in hexanes) to give tert-butyl3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₃ClFN₄O₂[M+H]⁺ 523.2, found 523.2.

The above tert-butyl3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(90 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL) and chargedwith HCl in dioxane (4N, 4 mL). The resulting mixture was stirred atroom temperature for 1 h. The solvent was evaporated in vacuo to give3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₄H₂₅ClFN₄ [M+H]⁺ 423.2,found 423.2.

Step d: Triethylamine (0.12 mL, 0.86 mmol) was added to a suspension of3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (23 mg, 0.05 mmol) and2-chloro-5-(trifluoromethyl)pyrimidine (50 mg, 0.27 mmol) in MeCN (1.3mL). The resulting mixture was stirred at 85° C. for 45 min. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 50% EtOAc in hexanes) to afford3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.53 (br s, 1H), 8.49 (br s, 2H), 7.30 (d,J=3.0 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.14 (d, J=6.4 Hz, 1H), 6.90 (d,J=7.2 Hz, 1H), 6.86 (d, J=9.6 Hz, 1H), 6.43 (t, J=2.8 Hz, 1H), 4.91 (d,J=16 Hz, 1H), 4.68 (d, J=16 Hz, 1H), 4.40 (m, 1H), 4.34 (m, 1H), 3.05(t, J=5.8, 2H), 2.50 (m, 1H), 2.40 (m, 1H), 2.15 (sextet, J=7.5 Hz, 1H),1.93 (sextet, J=7.5 Hz, 1H), 1.21 (t, J=7.6 Hz, 3H), 0.76 (t, J=7.4 Hz,3H). MS: (ES) m/z calculated for C₂₉H₂₆ClF₄N₆[M+H]⁺ 569.2, found 569.2.

Example 41 Synthesis of3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of 5-bromo-2-fluoropyridine (10 g, 57 mmol),4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (16 g, 93mmol), and sodium carbonate (18 g, 17 mmol) in a mixture of dioxane (150mL) and water (45 mL) was added Pd(dppf)Cl₂ complex with dichloromethane(2.0 g, 2.4 mmol). The reaction mixture was degassed (N₂) for 2 min andrefluxed for 1.5 h. Dioxane was removed in vacuo and the residue wastaken up in ether and water. The organic phase was separated and washedwith brine. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (hexane) toobtain 2-fluoro-5-(1-methylethenyl)pyridine. ¹H NMR (400 MHz, CDCl₃) δ8.28 (d, J=2.3 Hz, 1H), 7.82-7.88 (m, 1H), 6.89 (dd, J=3.0, 8.8 Hz, 1H),5.36 (s, 1H), 5.16 (s, 1H), 2.15 (s, 3H).

To the above 2-fluoro-5-(1-methylethenyl)pyridine (7.3 g, 53 mmol)dissolved in EtOAc (100 mL) was added 10% Pd/C (Degussa type E101 NE/W,700 mg), and the mixture was stirred under one atmosphere of hydrogenfor 4 h. Upon completion, the mixture was filtered through Celite andsolvent was removed in vacuo to give 2-fluoro-5-(1-methylethyl)pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.59-7.66 (dd, J=3.0, 8.4 Hz,1H), 2.88-3.00 (m, 1H), 1.26 (d, J=6.8 Hz, 6H).

Step b: N,N-diisopropylethylamine (0.050 mL, 0.23 mmol) was added to asuspension of3-(7-chloro-5-fluoro-1H-indol-4-yl)-2(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (58 mg, 0.13 mmol), 2-fluoro-5-(1-methylethyl)pyridine(240 mg, 1.7 mmol) and Li₂CO₃ (28 mg, 0.38 mmol) in DMSO (0.5 mL) undermagnetic stirring. The resulting mixture was stirred at 140° C.temperature for 4 d. The solvent was removed in vacuo and the residuewas purified by silica gel flash chromatography (10 to 100% MTBE inhexanes) followed by HPLC (MeCN/H₂O with 0.1% TFA) to obtain3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 7.92 (d, J=2.5 Hz, 1H), 7.45-7.52 (m, 2H),7.18-7.28 (m, 2H), 6.94 (d, J=7.2 Hz, 1H), 6.86 (d, J=10 Hz, 1H), 6.82(d, J=9.2 Hz, 1H), 6.42 (d, J=3.1 Hz, 1H), 4.58 (d, J=16 Hz, 1H), 4.27(d, J=16 Hz, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.01 (t, J=6.0 Hz, 2H),2.76-2.87 (m, 1H), 1.86-2.5 (m, 4H), 1.18-1.26 (m, 9H), 0.72 (t, J=7.6Hz, 3H)). MS: (ES) m/z calculated for C₃₂H₃₄ClFN₅ [M+H]⁺ 542.2, found542.2.

Example 42 Synthesis of3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.050 mL, 0.29 mmol) was added to asuspension of3-(7-chloro-5-fluoro-1H-indol-4-yl)-2(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (77 mg, 0.17 mmol), 2,3-difluoro-5-(1-methylethyl)pyridine(200 mg, 1.3 mmol) and Li₂CO₃ (42 mg, 0.30 mmol) in DMSO (0.5 mL) undermagnetic stirring. The resulting mixture was stirred at 140° C.temperature for 6 h. The solvent was removed in vacuo and the residuewas purified by silica gel flash chromatography (4 to 60% MTBE inhexanes) to obtain3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 7.89 (s, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.43 (d,J=14 Hz, 1H), 7.27-7.37 (m, 2H), 7.03 (d, J=6.8 Hz, 1H), 6.93 (d, J=10Hz, 1H), 6.56 (d, J=3.0 Hz, 1H), 4.63 (d, J=16 Hz, 1H), 4.23 (d, J=16Hz, 1H), 3.83-4.05 (m, 2H), 3.12 (t, J=6.0 Hz, 2H), 1.96-2.5 (m, 4H),1.25-1.37 (m, 9H), 0.81 (t, J=7.2 Hz, 3H). MS: (ES) m/z calculated forC₃₂H₃₃ClF₂N₅[M+H]⁺ 560.2, found 560.2.

Example 43 Synthesis of3-(7-chloro-5-fluoro-1H-indol-4-yl)-5-(5-cyclopropylpyrimidin-2-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (30 mg, 0.07 mmol), 2-chloro-5-cyclopropylpyrimidine (20mg, 0.13 mmol), and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (5 mL) undermagnetic stirring. The resulting mixture was stirred at 100° C. for 2 h.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by Preparative TLC(45% EtOAc in hexanes) followed by trituration in MeOH to afford3-(7-chloro-5-fluoro-1H-indol-4-yl)-5-(5-cyclopropylpyrimidin-2-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=2.7 Hz, 1H), 8.12 (s, 2H),7.12-7.32 (m, 5H), 6.87 (dd, J=8.5, 15.4 Hz, 1H), 6.47 (t, J=2.5 Hz,1H), 4.76 (d, J=15.9 Hz, 1H), 4.61 (d, J=15.9 Hz, 1H), 4.38 (m, 1H),4.18 (m, 1H), 3.03 (t, J=5.9 Hz, 2H), 1.91-2.54 (br,m, 4H), 1.66 (m,1H), 1.23 (t, J=7.5 Hz, 3H), 0.89 (m, 2H), 0.76 (t, J=7.5 Hz, 3H), 0.58(m, 2H). MS: (ES) m/z calculated C₃₁H₃₁ClFN₆ [M+H]⁺ 541.2, found 541.2.

Example 44 Synthesis of(2-(3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl)pyrimidin-5-yl)(pyrrolidin-1-yl)methanone

Step a: Oxalyl chloride (1 mL, 11.8 mmol) was added to a mixture of2-chloropyrimidine-5-carboxylic acid (500 mg, 3.2 mmol) indichloromethane (10 mL) followed by DMF (0.1 mL). The resulting mixturewas stirred at room temperature for 1 h. After removal of solvent underreduced pressure, the residue was dissolved in dichloromethane (5 mL).

To above acid chloride solution was added slowly to a solution ofpyrrolidine (1 mL) and DIEA (1 mL, 5.8 mmol) in dichloromethane (20 mL)at at −40° C. The resulting mixture was stirred at −40° C. for 1 h andquenched with aqueous citric acid solution. The reaction mixture wasdiluted with dichloromethane, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure to give(2-chloropyrimidin-5-yl)(pyrrolidin-1-yl)methanone. MS: (ES) m/zcalculated for C₉H₁₁ClN₃O [M+H]⁺ 212.1, found 212.1.

N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspensionof3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (45 mg, 0.11 mmol),(2-chloropyrimidin-5-yl)(pyrrolidin-1-yl)methanone (80 mg, 0.38 mmol),and Li₂CO₃ (30 mg, 0.41 mmol) in DMSO (5 mL) under magnetic stirring.The resulting mixture was stirred at 85° C. for 2 h. After cooling toroom temperature, the reaction mixture was diluted with EtOAc, washedwith brine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by Preparative TLC (75% EtOAc inhexanes) followed by trituration in MeOH to afford(2-(3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl)pyrimidin-5-yl)(pyrrolidin-1-yl)methanone.¹H NMR (400 MHz, CDCl₃) δ 8.56 (2, 2H), 2H), 8.54 (s, 1H), 7.13-7.32 (m,3H), 6.84-6.90 (m, 2H), 6.44 (dd, J=2.2, 3.2 Hz, 1H), 4.87 (d, J=16.0Hz, 1H), 4.68 (d, J=16.0 Hz, 1H), 4.24-4.47 (m, 2H), 3.48-3.63 (m, 6H),3.05 (t, J=6.0, 2H), 2.40-2.51 (m, 2H), 1.92-2.17 (m, 4H), 1.23 (t,J=8.0 Hz, 3H), 0.76 (t, J=8.0 Hz, 3H). MS: (ES) m/z calculatedC₃₃H₃₄ClFN₇O [M+H]⁺ 598.2, found 598.2.

Example 45 Synthesis of3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-[5-(pyrrolidin-1-ylmethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

To a mixture of[2-[3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]pyrimidin-5-yl]-pyrrolidin-1-yl-methanone(0.025 g, 0.042 mmol) in THF (2 mL) was added a solution of LiAlH₄ inether (2 M, 0.15 mL, 0.30 mmol). The resulting mixture was stirred for30 min at room temperature. It was then quenched with water and dilutedwith EtOAc. The organic layer was separated, dried over Na₂SO₄,concentrated under reduced pressure and purified by silica gel flashchromatography (0 to 30% MeOH in DCM) to yield3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-[5-(pyrrolidin-1-ylmethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.51 (br s, 1H), 8.28 (s, 2H), 7.30 (t, J=5.6Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.15 (m, 1H), 6.87 (d, J=7.6 Hz, 1H),6.84 (d, J=10 Hz, 1H), 6.46 (dd, J=2.8, 2.8 Hz, 1H), 4.80 (d, J=16 Hz,1H),), 4.62 (d, J=15.6 Hz, 1H), 4.39 (m, 1H), 4.22 (m, 1H), 3.50 (br s,2H),), 3.03 (t, J=5.8 Hz, 2H), 2.36-2.60 (m, 6H), 2.15 (sextet, J=7.6Hz, 1H), 1.92 (sextet, J=7.6 Hz, 1H), 1.81 (br s, 4H), 1.22 (t, J=7.6Hz, 3H), 0.74 (t, J=7.6 Hz, 3H). MS: (ES) m/z calculated for C₃₃H₃₆ClFN₇[M+H]⁺ 584.2, found 584.2.

Example 46 Synthesis of3-(7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) was added to a suspensionof3-(7-methyl-1H-indol-4-yl)-2(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (51 mg, 0.12 mmol), 2-fluoro-5-(1-methylethyl)pyridine(100 mg, 0.73 mmol) and Li₂CO₃ (24 mg, 0.32 mmol) in DMSO (0.25 mL)under magnetic stirring. The resulting mixture was stirred at 140° C.temperature for 23 h. The solvent was removed in vacuo and the residuewas purified by silica gel flash chromatography (0 to 70% MTBE inhexanes) to obtain3-(7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 7.91 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.34 (d,J=2.9 Hz, 1H), 7.08 (br s, 2H), 6.74 (d, J=9.2 Hz, 1H), 6.68 (d, J=7.6Hz, 1H), 6.48 (d, J=7.2 Hz, 1H), 6.40 (d, J=3.1 Hz, 1H), 4.43 (s, 2H),4.03 (t, J=5.6 Hz, 2H), 2.99 (t, J=5.6 Hz, 2H), 2.75-2.85 (m, 1H), 2.45(s, 3H), 2.06-2.40 (br s, 4H), 1.17-1.24 (m, 6H), 0.79-1.13 (br s, 6H).MS: (ES) m/z calculated for C₃₃H₃₈N₅[M+H]⁺ 504.3, found 504.3.

Example 47 Synthesis of3-(7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.050 mL, 0.29 mmol) was added to asuspension of3-(7-methyl-1H-indol-4-yl)-2(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (49 mg, 0.12 mmol), 2,3-difluoro-5-(1-methylethyl)pyridine(100 mg, 0.64 mmol) and Li₂CO₃ (34 mg, 0.46 mmol) in DMSO (0.50 mL)under magnetic stirring. The resulting mixture was stirred at 130° C.temperature for 23 h. The solvent was removed in vacuo and the residuewas purified by silica gel flash chromatography (0 to 70% MTBE inhexanes) to obtain3-(7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 7.91 (s, 1H), 7.30-7.35 (m, 2H), 7.24 (t,J=7.6 Hz, 1H), 7.09 (br s, 2H), 6.67 (d, J=7.6 Hz, 1H), 6.48 (d, J=7.6Hz, 1H), 6.43 (d, J=3.1 Hz, 1H), 4.38 (br s, 2H), 3.84 (t, J=5.6 Hz,2H), 3.03 (t, J=5.6 Hz, 2H), 2.83-2.92 (m, 1H), 2.44 (s, 3H), 2.33 (brs, 4H), 1.22 (d, J=7.2 Hz, 6H), 0.99 (br s, 6H). MS: (ES) m/z calculatedfor C₃₃H₃₇N₅[M+H]⁺ 522.3, found 522.3.

Example 48 Synthesis of3-(7-chloro-3-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: 1-Propenylmagnesium bromide solution in THF (0.5 M, 50 mL, 25mmol) was added rapidly to a solution of 5-bromo-2-chloronitrobenzene(2.0 g, 8.5 mmol) in anhydrous THF (100 mL) under N₂ and vigorouslystirred at −60° C. The reaction mixture was stirred at −40 to −50° C.for 35 minutes, then quenched with saturated NH₄Cl solution and 100 mLwater and allowed to warm to room temperature. The organic phase wasseparated, and the aqueous phase was extracted with ether. The combinedorganic phases were washed with brine and the solvent was removed underreduced pressure. The residue was purified by silica gel flashchromatography (2 to 4% MTBE in hexanes) to obtain4-bromo-7-chloro-3-methyl-1H-indole. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (brs, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.04 (s, 1H), 6.99 (d, J=8.4 Hz, 1H),2.54 (s, 3H).

Step b: To a suspension of 4-bromo-7-chloro-3-methyl-1H-indole (420 mg,1.7 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(650 mg, 2.6 mmol), and KOAc (500 mg, 5.1 mmol) in dioxane (4 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (250 mg, 0.31 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for3 h. The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (0 to 4% MTBE in hexanes) togive7-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₅H₂₀BClNO₂ [M+H]⁺ 292.1, found 292.1.

Step c: To a suspension of3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(51 mg, 0.10 mmol),7-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(52 mg, 0.18 mmol), K₂CO₃ (43 mg, 0.31 mmol) in p-dioxane (3 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (31 mg,0.038 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 1 h. The solvent was removed underreduced pressure and the residue was purified by silica gel flashchromatography (12% EtOAc in hexanes) followed by trituration withmethanol to give3-(7-chloro-3-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, d₆-DMSO) δ 11.45 (s, 1H), 8.27 (s, 1H), 7.95 (d, J=14Hz, 1H), 7.31 (s, 1H), 7.20-7.28 (m, 2H), 6.97 (d, J=8.0 Hz, 1H), 6.93(d, J=6.0 Hz, 1H), 6.38 (d, J=8.0 Hz, 1H), 4.49 (d, J=16 Hz, 1H), 4.18(d, J=16 Hz, 1H), 3.85-4.04 (m, 2H), 2.90-3.16 (m, 2H), 2.11-2.45 (m,3H), 2.01 (s, 3H), 1.89-2.00 (m, 1H), 1.20 (t, J=7.6 Hz, 3H), 0.71 (t,J=7.6 Hz, 3H). MS: (ES) m/z calculated for C₃₁H₂₉ClF₄N₅[M+H]⁺ 582.2,found 582.2.

Example 49 Synthesis of3-(7-fluoro-3-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a solution of 4-bromo-7-fluoro-1H-indole (1.0 g, 4.7 mmol) inDMF (5 mL) was added N-chlorosuccinimide (690 mg, 5.2 mmol), and themixture was stirred for 2 h. When the reaction was complete, the mixturewas diluted in EtOAc and water, the organic phase was separated andEtOAc was removed under reduced pressure. The residue was purified bysilica gel flash chromatography (4 to 20% MTBE in hexanes) to give4-bromo-3-chloro-7-fluoro-1H-indole. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (brs, 1H), 7.27 (d, J=2.9 Hz, 1H), 7.22 (dd, J=4.4, 8.4 Hz, 1H), 6.81 (dd,J=8.4 Hz, 10, 1H).

Step b: To a suspension of 4-bromo-3-chloro-7-fluoro-1H-indole (810 mg,3.3 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(920 mg, 3.6 mmol), and KOAc (980 mg, 10 mmol) in dioxane (15 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (820 mg, 1.0 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for1 h. The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (2 to 20% EtOAc in hexanes)to give3-chloro-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.¹H NMR (400 MHz, d₆-DMSO) δ 12.00 (s, 1H), 7.63 (d, J=2.7 Hz, 1H), 7.24(dd, J=5.2, 8.0 Hz, 1H), 7.01 (dd, J=8.0, 12 Hz, 1H), 1.33 (s, 12H).

Step c: To a suspension of3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(52 mg, 0.10 mmol),3-chloro-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(50 mg, 0.16 mmol), K₂CO₃ (51 mg, 0.37 mmol) in p-dioxane (3 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (39 mg,0.048 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 1 h. The solvent was removed underreduced pressure and the residue was purified by silica gel flashchromatography (4 to 60% EtOAc in hexanes) followed by trituration withmethanol to give3-(3-chloro-7-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H), 7.62 (dd, J=2.0, 13 Hz, 1H),7.44 (s, 1H), 7.22-7.29 (m, 2H), 6.96 (dd, J=2.6, 6.8 Hz, 1H), 6.75 (dd,J=8.8, 11 Hz, 1H), 6.56 (dd, J=4.8, 8.8 Hz, 1H), 4.75 (d, J=15 Hz, 1H),4.37 (d, J=15 Hz, 1H), 3.97-4.15 (m, 2H), 3.01-3.10 (m, 2H), 2.29-2.54(m, 3H), 2.01-2.15 (m, 1H), 1.30 (t, J=7.2, 3H), 0.77 (t, J=7.2 Hz, 3H).MS: (ES) m/z calculated for C₃₀H₂₆ClF₅N₅[M+H]⁺ 586.2, found 586.2.

Example 50 Synthesis of3-(3-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a solution of 4-bromo-7-methyl-1H-indole (750 mg, 3.6 mmol)in DMF (5 mL) was added N-chlorosuccinimide (500 mg, 3.7 mmol), and themixture was stirred for 3 h. When the reaction was complete, the mixturewas diluted in EtOAc and water, the organic phase was separated andEtOAc was removed under reduced pressure. The residue was purified bysilica gel flash chromatography (4 to 20% MTBE in hexanes) to give4-bromo-3-chloro-7-methyl-1H-indole. ¹H NMR (400 MHz, d₆-DMSO) δ 11.68(s, 1H), 7.62 (d, J=2.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 2.41 (s, 3H).

Step b: To a suspension of 4-bromo-3-chloro-7-methyl-1H-indole (700 mg,2.9 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(870 mg, 3.4 mmol), and KOAc (1.1 g, 11 mmol) in dioxane (7 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (350 mg, 0.42 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 100° C. for14 h. The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (4 to 30% MTBE in hexanes)to give3-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.¹H NMR (400 MHz, d₆-DMSO) δ 11.38 (s, 1H), 7.51 (d, J=2.6 Hz, 1H), 7.17(d, J=7.2 Hz, 1H), 6.95 (d, J=7.2 Hz, 1H), 2.46 (s, 3H), 1.33 (s, 12H).

Step c: To a suspension of3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(56 mg, 0.11 mmol),3-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(60 mg, 0.21 mmol), K₂CO₃ (51 mg, 0.37 mmol) in p-dioxane (3 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (53 mg,0.064 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 3.5 h. The solvent was removed underreduced pressure and the residue was purified by silica gel flashchromatography (4 to 14% EtOAc in hexanes) followed by HPLC (MeCN/H₂Owith 0.1% TFA) to give3-(3-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H), 7.61 (d, J=14 Hz, 1H), 7.35 (s,1H), 7.22-7.26 (m, 2H), 6.94 (dd, J=3.4, 6.4 Hz, 1H), 6.77 (d, J=7.2 Hz,1H), 6.51 (d, J=7.2 Hz, 1H), 4.76 (d, J=16 Hz, 1H), 4.34 (d, J=16 Hz,1H), 3.94-4.14 (m, 2H), 2.98-3.10 (m, 2H), 2.33-2.55 (m, 3H), 2.43 (s,3H), 2.03-2.16 (m, 1H), 1.30 (t, J=8.0 Hz, 3H), 0.77 (t, J=8.0 Hz, 3H).MS: (ES) m/z calculated for C₃₁H₂₉ClF₄N₅[M+H]⁺ 582.2, found 582.2.

Example 51 Synthesis of3-(7-chloro-1H-indol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: N,N-diisopropylethylamine (6 mL, 34.5 mmol) was added to amixture of (2,6-dimethylphenyl)hydrazine hydrochloride (5 g, 28.9 mmol),tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (5 g, 22.3 mmol) andEtOH (60 mL) in a 250 mL round bottom flask under magnetic stirring. Theresulting mixture was stirred under reflux for 3 h. Glacial acetic acid(6 mL, 104 mmol) was added and the mixture was stirred under reflux foranother 2 h. After removal of solvent under reduced pressure, theresidue was dissolved in EtOAc and washed with aqueous NaOH (2N), brineand dried over MgSO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (5 to 55%EtOAc in hexanes) to give tert-butyl3-amino-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₁₉H₂₇N₄O₂ [M+H]⁺ 343.2, found 343.2.

Caution: Diazonium Formation could be Potentially Dangerous, PleaseHandle with Care and Ware Proper Personal Protection Equipment!

Step b: Isopentyl nitrite (96%, 4 mL, 28.6 mmol) was added slowly atroom temperature to a mixture of tert-butyl3-amino-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(3 g, 8.8 mmol), CuBr (4 g, 27.9 mmol) and MeCN (50 mL) in a 250 mLround bottom flask under magnetic stirring. The resulting mixture wasstirred at room temperature for 1 h, diluted with EtOAc, filteredthrough Celite, washed with sat NH₄Cl solution, and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (2 to 25% EtOAc in hexanes)to give tert-butyl3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. MS: (ES) m/z calculated for C₁₉H₂₅BrN₃O₂[M+H]⁺ 406.1,found 406.1.

Step c: tert-butyl3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(1.5 g, 3.7 mmol), was dissolved in dichloromethane (10 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. After the reaction was complete, the solventwas evaporated in vacuo to give3-bromo-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₁₄H₁₇BrN₃ [M+H]⁺ 306.1,found 306.1.

N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspensionof3-bromo-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (1 g, 2.9 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine(1.1 g, 6 mmol), and K₂CO₃ (1.38 g, 10 mmol) in MeCN (10 mL) undermagnetic stirring. The resulting mixture was stirred at 85° C. for 2 h.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by silica gel flashchromatography (2 to 15% EtOAc in hexanes) to afford3-bromo-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.MS: (ES) m/z calculated for C₂₀H₁₇BrF₄N₄[M+H]⁺ 469.1, found 469.1.

Step d: To a suspension of3-bromo-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(50 mg, 0.11 mmol),7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (50mg, 0.18 mmol), and K₂CO₃ (180 mg, 1.3 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (40 mg,0.05 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give3-(7-chloro-1H-indol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J=1.3 Hz, 1H), 7.64 (dd, J=2.0, 13.5Hz, 1H), 7.44 (d, J=3.2 Hz, 1H), 7.15 (t, J=7.6 Hz, 2H), 7.04 (br s,2H), 6.94 (d, J=7.9 Hz, 1H), 6.52-6.57 (m, 2H), 4.65 (s, 2H), 4.11 (t,J=5.8 Hz, 2H), 3.29 (s, 1H), 3.06 (t, J=5.8 Hz, 2H), 1.96 (br m, 6H).MS: (ES) m/z calculated C₂₈H₂₃ClF₄N₅[M+H]⁺ 540.2, found 540.2.

Example 52 Synthesis of3-(3-chloro-7-fluoro-1H-indol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of3-bromo-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(100 mg, 0.22 mmol),7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (100mg, 0.38 mmol), K₂CO₃ (200 mg, 1.45 mmol) in p-dioxane (6 mL) and water(1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (50 mg, 0.06mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by by Preparative TLC (40% EtOAc in hexanes) followed by HPLC(MeCN/H₂O, with 0.1% TFA) to give2-(2,6-dimethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 8.19 (dt, J=1.1, 1.9 Hz, 1H),7.39 (dd, J=2.0, 13.2 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 7.08 (t, J=7.5Hz, 1H), 6.96 (br, 2H), 6.70 (dd, J=8.1, 10.7 Hz, 1H), 6.50-6.59 (m,2H), 4.64 (s, 2H), 4.07 (t, J=5.8 Hz, 2H), 3.12 (t, J=5.8 Hz, 2H), 1.96(br m, 6H). MS: (ES) m/z calculated C₂₈H₂₃F₅N₅ [M+H]⁺ 524.2, found524.2.

Step b: N-chlorosuccinimide (33 mg, 0.25 mmol) was added to a solutionof2-(2,6-dimethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(30 mg, 0.06 mmol) in DMF (5 mL). The resulting mixture was stirred at60° C. for 6 h. After cooling to room temperature, the reaction mixturewas diluted with EtOAc, washed with brine and dried over MgSO₄. Thesolvent was removed under reduced pressure and the residue was purifiedby Preparative TLC (40% EtOAc in hexanes) followed by HPLC (MeCN/H₂O,with 0.1% TFA) to afford3-(3-chloro-7-fluoro-1H-indol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.16 (dt, J=1.0, 2.0 Hz, 1H),7.18-7.41 (m, 2H), 7.03-7.13 (m, 2H), 6.70-6.86 (m, 2H), 6.58 (ddd,J=0.7, 4.6, 8.2 Hz, 1H),), 4.71 (d, J=15.5 Hz, 1H), 4.48 (d, J=15.5 Hz,1H), 3.84-4.21 (m, 2H), 3.06-3.21 (m, 2H), 2.22 (d, J=0.7 Hz, 3H), 1.87(d, J=0.7 Hz, 3H). MS: (ES) m/z calculated C₂₈H₂₂ClF₅N₅[M+H]⁺ 558.1,found 558.2.

Example 53 Synthesis of2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of tert-butyl3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(440 mg, 1.08 mmol),6-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(260 mg, 0.94 mmol), K₂CO₃ (500 mg, 3.6 mmol) in p-dioxane (6 mL) andwater (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (200 mg,0.24 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give tert-butyl2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₈H₃₂FN₄O₂[M+H]⁺ 475.2, found 475.2.

The above tert-butyl2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylatewas dissolved in dichloromethane (5 mL) and charged with HCl in dioxane(4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the reaction was complete, the solvent was evaporated in vacuoto give2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₃H₂₄FN₄ [M+H]⁺ 375.2, found375.2.

Step b: N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to asuspension of2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.12 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine(45 mg, 0.25 mmol), and Li₂CO₃ (30 mg, 0.41 mmol) in DMSO (5 mL) undermagnetic stirring. The resulting mixture was stirred at 75° C. for 30min. After cooling to room temperature, the reaction mixture was dilutedwith EtOAc, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified byPreparative TLC (40% EtOAc in hexanes) followed followed by HPLC(MeCN/H₂O, with 0.1% TFA) to afford2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 2H), 8.25 (s, 1H), 7.04-7.18 (m, 3H),6.46-6.53 (m, 1H), 4.91 (s, 2H), 4.42 (br, 2H), 3.11 (t, J=5.8 Hz, 2H),2.42 (d, J=1.7 Hz, 3H), 1.92-2.13 (br m, 6H). MS: (ES) m/z calculatedC₂₈H₂₅F₄N₆ [M+H]⁺ 521.2, found 521.2.

Example 54 Synthesis of3-(5-fluoro-7-methyl-1H-indol-4-yl)-2-(2,6-dimethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of tert-butyl3-bromo-2-(2,5-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(430 mg, 1.0 mmol),5-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(220 mg, 0.80 mmol), and K₂CO₃ (420 mg, 3.0 mmol) in p-dioxane (8 mL)and water (2 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (250mg, 0.30 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 15 h. The reaction mixture was dilutedwith dichloromethane, dried over Na₂SO₄ and filtered through Celite. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel flash chromatography (10 to 60% MTBE in hexanes) to givetert-butyl3-(5-fluoro-7-methyl-1H-indazol-4-yl)-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5-(4H)-carboxylate.MS: (ES) m/z calculated for C₂₈H₃₂FN₄O₂[M+H]⁺ 475.3, found 475.3.

The above tert-butyl3-(5-fluoro-7-methyl-1H-indazol-4-yl)-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5-(4H)-carboxylatewas dissolved in dichloromethane (50 mL) and treated with HCl in dioxane(4N, 4 mL). The resulting mixture was stirred at room temperature for 1d. After the reaction was complete, the solvent was evaporated in vacuoto give3-(5-fluoro-7-methyl-1H-indazol-4-yl)-2(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₃H₂₄FN₄ [M+H]⁺ 375.2, found375.2.

Step b: N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) was added to asuspension of3-(5-fluoro-7-methyl-1H-indazol-4-yl)-2(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (48 mg, 0.12 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine(25 mg, 0.14 mmol) and Li₂CO₃ (20 mg, 0.27 mmol) in acetonitrile (1 mL)under magnetic stirring. The resulting mixture was stirred at 80° C. for4 h. The solvent was removed in vacuo and the residue was purified bysilica gel flash chromatography (4 to 100% MTBE in hexanes) followed bytrituration with MTBE in hexanes to obtain3-(5-fluoro-7-methyl-1H-indazol-4-yl)-2-(2,6-dimethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 8.57 (br s, 2H), 7.38 (d, J=3.0 Hz, 1H), 7.10(d, J=4.8 Hz, 2H), 6.84 (t, J=4.8 Hz, 1H), 6.58 (d, J=11 Hz, 1H), 6.33(d, J=3.0 Hz, 1H), 4.3-4.5 (m, 2H), 3.00 (t, J=5.4 Hz, 2H), 2.48 (s,3H), 2.18 (s, 3H), 1.70 (s, 3H). MS: (ES) m/z calculated for C₂₈H₂₅F₄N₆[M+H]⁺ 521.2, found 521.2.

Example 55 Synthesis of3-(5-fluoro-7-methyl-1H-indazol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) was added to asuspension of3-(5-fluoro-7-methyl-1H-indazol-4-yl)-2(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (48 mg, 0.12 mmol) and2,3-difluoro-5-(trifluoromethyl)pyridine (94 mg, 0.51 mmol) inacetonitrile (1 mL) under magnetic stirring. The resulting mixture wasstirred at 80° C. for 4 h. The solvent was removed in vacuo and theresidue was purified by silica gel flash chromatography (0 to 60% MTBEin hexanes) followed by trituration with MTBE in hexanes to obtain3-(5-fluoro-7-methyl-1H-indazol-4-yl)-2-(2,6-dimethylphenyl)-5-(2-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 8.21 (s, 1H), 7.63 (dd, J=1.9, 13 Hz, 1H),7.10 (d, J=4.8 Hz, 2H), 6.84 (t, J=4.8 Hz, 1H), 6.57 (d, J=12 Hz, 1H),6.32 (d, J=2.9 Hz, 1H), 4.78 (d, J=16 Hz, 1H), 4.40 (d, J=16 Hz, 1H),4.10 (t, J=5.6 Hz, 2H), 3.07 (t, J=5.6 Hz, 2H), 2.47 (s, 3H), 2.18 (s,3H), 1.70 (s, 3H). MS: (ES) m/z calculated for C₂₉H₂₅F₅N₅ [M+H]⁺ 538.2,found 538.2.

Example 56 Synthesis of3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of tert-butyl3-bromo-2-(2,5-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(500 mg, 1.2 mmol),7-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(470 mg, 1.6 mmol), and K₂CO₃ (500 mg, 3.6 mmol) in p-dioxane (10 mL)and water (2 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (300mg, 0.37 mmol). The reaction mixture was degassed (N₂) for 2 min andstirred under N₂ at 100° C. for 2.5 h. The reaction mixture was dilutedwith EtOAc and filtered through Celite. The organic phase was separated,the solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (10 to 60% EtOAc in hexanes)to give tert-butyl3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5-(4H)-carboxylate.MS: (ES) m/z calculated for C₂₇H₂₉ClFN₄O₂[M+H]⁺ 495.2, found 495.2.

The above tert-butyl3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5-(4H)-carboxylatewas dissolved in dichloromethane (50 mL) and treated with HCl in dioxane(4N, 5 mL). The resulting mixture was stirred at room temperature for 16h. After the reaction was complete, the solvent was evaporated in vacuoto give3-(7-chloro-5-fluoro-1H-indol-4-yl)-2(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₂H₂₁ClFN₄ [M+H]⁺ 395.1,found 395.1.

Step b: N,N-diisopropylethylamine (0.04 mL, 0.23 mmol) was added to asuspension of3-(7-chloro-5-fluoro-1H-indol-4-yl)-2(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (48 mg, 0.12 mmol), 2,3-difluoro-5-(1-methylethyl)pyridine(50 mg, 0.32 mmol) and Li₂CO₃ (20 mg, 0.27 mmol) in DMSO (1 mL) undermagnetic stirring. The resulting mixture was stirred at 140° C.temperature for 14 h. The solvent was removed in vacuo and the residuewas purified by silica gel flash chromatography (4 to 100% MTBE inhexanes) followed by HPLC (MeCN/H₂O with 0.1% TFA) to obtain3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(1-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 7.54 (d, J=3.0 Hz, 1H), 7.42(dd, J=1.8, 14 Hz, 1H), 7.21 (d, J=4.8 Hz, 2H), 6.9-7.0 (m, 2H), 6.57(d, J=3.3 Hz, 1H), 4.64 (d, J=16 Hz, 1H), 4.23 (d, J=16 Hz, 1H), 3.8-4.1(m, 2H), 3.13 (t, J=6.0 Hz, 2H), 2.9-3.0 (m, 1H), 2.28 (s, 3H), 1.78 (s,3H), 1.31 (d, J=7.2 Hz, 6H). MS: (ES) m/z calculated forC₃₀H₂₉ClF₂N₅[M+H]⁺ 532.2, found 532.2.

Example 57 Synthesis of5-(3,5-dichloro-2-pyridyl)-2-(2,6-dimethylphenyl)-3-(1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine

Step a: tert-butyl3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(1.5 g, 3.7 mmol) was dissolved in dichloromethane (10 mL) and chargedwith HCl in dioxane (4N, 5 mL). The resulting mixture was stirred atroom temperature for 2 h. After the reaction was complete, the solventwas evaporated in vacuo to give3-bromo-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₁₄H₁₇BrN₃ [M+H]⁺ 306.1,found 306.1.

N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspensionof3-bromo-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (1 g, 2.9 mmol), 3,5-dichloro-2-fluoropyridine (1.1 g, 6.6mmol), and K₂CO₃ (1.38 g, 10 mmol) in MeCN (10 mL) under magneticstirring. The resulting mixture was stirred at 90° C. for 2 h. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by silica gel flashchromatography (2 to 25% EtOAc in hexanes) to afford3-bromo-5-(3,5-dichloropyridin-2-yl)-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.MS: (ES) m/z calculated for C₁₉H₁₈BrCl₂N₄[M+H]⁺ 451.0, found 451.1.

Step b: To a degassed solution of3-bromo-5-(3,5-dichloropyridin-2-yl)-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(80 mg, 0.18 mmol), indole-4-boronic acid (26 mg, 0.18 mmol), and sodiumcarbonate (47 mg, 0.44 mmol) in dioxane (5 mL) and water (2 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (13 mg, 0.018 mmol). Themixture was purged with nitrogen and heated to 80° C. After 18 h, themixture was cooled to room temperature and diluted with EtOAc (20 mL).The organic layer was washed with water (20 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude material was passedthrough a silica gel plug and rinsed with EtOAc. The filtrate wasconcentrated and purified by reverse phase HPLC (MeCN/H₂O, with 0.1%TFA) to afford the titled compound. ¹H NMR (400 MHz, CD₃OD) δ 8.13 (ddd,J=15.9, 2.3, 0.6 Hz, 1H), 7.86 (dd, J=2.3, 0.6 Hz, 1H), 7.46 (d, J=8.2Hz, 1H), 7.27 (t, J=7.7 Hz, 2H), 7.13 (br s, 1H), 7.01-6.94 (m, 2H),6.69 (d, J=7.3 Hz, 2H), 4.53 (s, 2H), 3.88 (t, J=5.7 Hz, 2H), 3.21 (t,J=5.7 Hz, 2H). 2.06 (br s, 6H), MS: (ES) m/z calculated for C₂₇H₂₃C₁₂N₅[M+H]⁺ 488.14, found 488.5.

Example 58 Synthesis of[4-[2-(2,6-dimethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanol

Step a: To a suspension of tert-butyl3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(90 mg, 0.22 mmol), methyl5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate(70 mg, 0.22 mmol) (intermediate Example 2), and K₂CO₃ (150 mg, 1.1mmol) in p-dioxane (3 mL) and water (0.5 mL) was added Pd(dppf)Cl₂complex with dichloromethane (70 mg, 0.085 mmol). The reaction mixturewas degassed (N₂) for 2 min and stirred under N₂ at 100° C. for 2 h. Thereaction mixture was diluted with EtOAc, washed with aqueous NaHCO₃ anddried over Na₂SO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (0 to 80%EtOAc in hexanes) to give tert-butyl2-(2,6-dimethylphenyl)-3-(5-fluoro-7-methoxycarbonyl-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₂FN₄O₄[M+H]⁺ 519.2, found 519.2.

Step b: The above tert-butyl2-(2,6-dimethylphenyl)-3-(5-fluoro-7-methoxycarbonyl-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(38 mg, 0.073 mmol) was dissolved in THF (3 mL) and charged with asolution of LiAlH₄ in ether (2 M, 0.15 mL, 0.30 mmol) at 0° C. Theresulting mixture was stirred at 0° C. for 20 min. It was then quenchedwith methanol and diluted with EtOAc and brine. The organic layer wasseparated, dried over Na₂SO₄, concentrated under reduced pressure andpurified by silica gel flash chromatography (0 to 100% EtOAc in hexanes)to give tert-butyl2-(2,6-dimethylphenyl)-3-[5-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₂₈H₃₂FN₄O₃[M+H]⁺ 491.2, found 491.2.

Step c: The above tert-butyl2-(2,6-dimethylphenyl)-3-[5-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(21 mg, 0.042 mmol) was dissolved in dichloromethane (1 mL) and chargedwith HCl in dioxane (4N, 3 mL). The resulting mixture was stirred atroom temperature for 1 h. The solvent was evaporated in vacuo to give[4-[2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanolhydrochloride. MS: (ES) m/z calculated for C₂₃H₂₄FN₄O [M+H]⁺ 391.2,found 391.2.

Step d: Triethylamine (0.12 mL, 0.85 mmol) was added to a suspension of[4-[2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanolhydrochloride (20 mg, 0.044 mmol) and2-chloro-5-(trifluoromethyl)pyrimidine (60 mg, 0.32 mmol) in MeCN (2mL). The resulting mixture was stirred at 85° C. for 30 min. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 90% EtOAc in hexanes) to afford[4-[2-(2,6-dimethylphenyl)-6-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanol.¹H NMR (400 MHz, CDCl₃) δ 8.46 (br s, 2H), 7.50 (s, 1H), 7.31 (d, J=2.8Hz, 1H), 7.03 (m, 2H), 6.76 (m, 1H), 6.72 (d, J=11 Hz, 1H), 6.32 (d,J=3.2 Hz, 1H), 4.84 (m, 2H), 4.64 (d, J=16 Hz, 1H), 4.43 (m, 1H), 4.25(m, 1H), 3.55-3.76 (m, 2H), 3.00 (t, J=5.6 Hz, 2H), 2.16 (s, 3H), 1.69(s, 3H). MS: (ES) m/z calculated for C₂₈H₂₅F₄N₆O [M+H]⁺ 537.2, found537.2.

Example 59 Synthesis of tert-butyl3-(6,7-dihydro-3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

Step a: A mixture of 3-methyl-2-nitro-phenol (50 g, 326 mmol),1-iodo-2-methyl-propane (184 g, 1 mol) and Cs₂CO₃ (326 g, 1 mol) inacetone (500 mL) was stirred overnight under reflux. It was then cooledto room temperature and filtered through Celite. The filtrate wascollected and concentrated under reduced pressure. The obtained solidwas redissolved into EtOAc, washed with brine, dried over Na₂SO₄ andconcentrated on a rotary evaporator under reduced pressure to afford1-isobutoxy-3-methyl-2-nitro-benzene. ¹H NMR (400 MHz, CDCl₃) δ 7.26 (t,J=8.0 Hz, 1H), 6.82 (m, 2H), 3.78 (d, J=6.8 Hz, 2H), 2.94 (s, 3H), 2.07(m, 1H), 0.98 (d, J=6.4 Hz, 6H).

Step b: A pressure vessel containing1-isobutoxy-3-methyl-2-nitro-benzene (130.4 g, 623 mmol), 10% Pd/C (25g, 50% wet) and EtOH (750 mL) was agitated under a hydrogen atmosphereat 45 psi for 3 h. It was then filtered through Celite. The filtrate wascollected and concentrated under reduced pressure to yield2-isobutoxy-6-methyl-aniline. C₁₁H₁₈NO [M+H]⁺ 180.2, found 180.2.

Caution: Diazonium Formation could be Potentially Dangerous, PleaseHandle with Care and Ware Proper Personal Protection Equipment!

Step c: To 100 mL of conc. HCl at −10° C. was added isobutoxy-6-methylaniline (26.4 g, 147 mmol) portionwise to obtain a stirrable suspension.After stirred for 30 min at the same temperature, a solution of NaNO₂(12.2 g, 176 mmol) in water (25 mL) was added dropwise within 20 min toobtain the diazonium salt.

To the above diazonium salt was added SnCl₂.2H₂O (83 g, 368 mmol) inconc. HCl (120 mL) portionwise. The obtained mixture was then stirredfor 10 min at −10° C. followed by 1 h at room temperature. The mixturewas then diluted into DCM (400 mL) and water. The organic layer wasseparated, dried over Na₂SO₄ and concentrated on a rotary evaporatorunder reduced pressure to yield (2-isobutoxy-6-methyl-phenyl)hydrazinehydrochloride. C₁₁H₁₉N₂O [M+H]⁺ 195.1, found 195.1.

Step d: To a stirred suspension of (2-isobutoxy-6-methylphenyl)hydrazinehydrochloride (8 g, 39.9 mmol) in EtOH (60 mL) and glacial acetic acid(12 mL, 208 mmol) was added tert-butyl3-cyano-4-oxopiperidine-1-carboxylate (5 g, 22.3 mmol) at roomtemperature. The resulting mixture was stirred under reflux for 16 h.After removal of solvent under reduced pressure, the residue wasdissolved in EtOAc and washed with aqueous NaOH (2 N), brine and driedover MgSO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (5 to 55% EtOAcin hexanes) to give tert-butyl3-amino-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₂H₃₃N₄O₃ [M+H]⁺ 401.2, found 401.2.

Caution. Diazonium Formation could be Potentially Dangerous, PleaseHandle with Care and Ware Proper Personal Protection Equipment!

Isoamyl nitrite (96%, 4 mL, 28.6 mmol) was added slowly at roomtemperature to a mixture oftert-butyl-3-amino-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(3 g, 8.1 mmol), CuBr (4 g, 27.9 mmol) and MeCN (50 mL) in a 250 mLround bottom flask under magnetic stirring. The resulting mixture wasstirred at room temperature for 1 h, diluted with EtOAc, filteredthrough Celite, washed with sat NH₄Cl solution, and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (2 to 25% EtOAc in hexanes)to give tert-butyl3-bromo-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₂H₃₁BrN₃O₃[M+H]⁺ 464.1, found 464.2.

Step e: To a suspension of tert-butyl3-bromo-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(125 mg, 0.32 mmol), 1H-indol-5-yl-5-boronic acid (74 mg, 0.48 mmol),and Na₂CO₃ (85 mg, 0.81 mmol) in p-dioxane (4 mL) and water (1 mL) wasadded Pd(dppf)Cl₂ complex with dichloromethane (26 mg, 0.032 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred under N₂ at 95°C. for 6 h. The reaction mixture was diluted with EtOAc, filteredthrough Celite, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (5 to 20% to 40% EtOAc in hexanes) to givetert-butyl3-(6,7-dihydro-3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.¹H NMR (400 MHz, CD₃OD) δ 7.40 (s, 1H), 7.20-7.26 (m, 3H), 6.92 (d,J=9.7 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.34 (d,J=3.1 Hz, 1H), 4.54-4.65 (m, 2H), 3.80-3.95 (m, 2H), 3.67-3.70 (m, 2H),2.85 (t, J=5.6 Hz, 2H), 1.96 (s, 3H), 1.80-1.90 (m, 1H), 1.47 (s, 9H),0.86 (dd, J=3.5, 6.6 Hz, 6H). MS: (ES) m/z calculated for C₃₀H₃₇N₄O₃[M+H]⁺ 501.28, found 501.2.

Example 60 Synthesis oftert-butyl-3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide

Step a: The abovetert-butyl-6,7-dihydro-3-(1H-indol-5-yl)-2-(2-isobutoxy-6methyl-phenyl)-2H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate wasdissolved in dichloromethane (5 mL) and TFA (4N, 5 mL) was added. Theresulting mixture was stirred at room temperature for 2 h. Aftercompletion of the reaction, the solvent was diluted with water andaqueous NaHCO₃ and extracted with dichloromethane (2×50 mL) washed withbrine and dried over MgSO₄. The solvent was removed under reducedpressure and dried under vacuum to give4,5,6,7-tetrahydro-3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine.MS: (ES) m/z calculated for C₂₅H₂₉ClN₄O [M+H]⁺ 401.2, found 401.3.

Step b: To a stirred solution of4,5,6,7-tetrahydro-3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine(30 mg, 0.074 mmol) in anhydrous THF (1.5 mL) were addedN,N-diisopropylethylamine (24 mg, 0.185 mmol) and tert-butyl isocyanate(10 mg, 0.089 mmol). The reaction mixture was stirred at roomtemperature for 16 h. After completion, the reaction mixture was dilutedwith EtOAc, washed with brine, and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by Prep HPLC(20-100% H₂O/ACN) and lyophilized to affordN-tert-butyl-6,7-dihydro-3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide.¹H NMR (400 MHz, CD₃OD) δ 7.44 (d, J=1.5 Hz, 1H), 7.21-7.26 (m, 3H),6.94 (dd, J=1.5, 8.6 Hz, 2H), 6.85 (d, J=8.2 Hz, 1H), 6.78 (d, J=7.6 Hz,1H), 6.35 (dd, J=3.2, 10.8 Hz, 1H), 4.54 (dd, J=15.2, 29.2 Hz, 2H),3.70-3.76 (m, 2H), 3.64-3.70 (m, 2H), 2.85 (t, J=5.6 Hz, 2H), 1.96 (s,3H), 1.80-1.90 (m, 1H), 1.32 (s, 9H), 0.86 (dd, J=3.5, 6.6 Hz, 6H). MS:(ES) m/z calculated C₃₀H₃₈N₅O₂ [M+H]⁺ 500.29, found 500.2.

Example 61 Synthesis of tert-butyl3-(6,7-dihydro-3-(1H-indol-5-yl)-2-(2-methoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

Step a: To a stirred suspension of 1-(2-methoxy-6-methylphenyl)hydrazinehydrochloride (3.77 g, 20.0 mmol) in EtOH (50 mL) and glacial aceticacid (10 mL, 208 mmol) was added tert-butyl3-cyano-4-oxopiperidine-1-carboxylate (4.5 g, 22.0 mmol) at roomtemperature. The resulting mixture was stirred under reflux for 16 h.After removal of solvent under reduced pressure, the residue wasdissolved in EtOAc and washed with aqueous NaOH (2 N), brine, and driedover MgSO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (5 to 55% EtOAcin hexanes) to give tert-butyl3-amino-2-(2-methoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₁₉H₂₇N₄O₃ [M+H]⁺ 359.2, found 359.2.

Caution. Diazonium Formation could be Potentially Dangerous, PleaseHandle with Care and Ware Proper Personal Protection Equipment!

Isoamyl nitrite (3.2 g, 27.8 mmol) was added slowly at room temperatureto a mixture oftert-butyl-3-amino-2-(2-methoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(5.0 g, 13.9 mmol), CH₂I₂(14.9 g, 55.7 mmol) and MeCN (60 mL) in a 250mL round bottom flask under magnetic stirring. The resulting mixture wasstirred at room temperature for 1 h, diluted with EtOAc, filteredthrough Celite, washed with sat NH₄Cl solution, and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (2 to 25% EtOAc in hexanes)to give tert-butyl3-iodo-2-(2-methoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₁₉H₂₅N₃O₃ [M+H]⁺ 469.1, found 469.3.

Step b: To a suspension of tert-butyl3-Iodo-2-(2-methoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(250 mg, 0.53 mmol), 1H-indol-5-yl-5-boronic acid (128 mg, 1.8 mmol),Na₂CO₃ (139 mg, 3.6 mmol) in p-dioxane (4 mL) and water (1 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (300 mg, 0.37 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred under N₂ at100° C. for 2 h. The reaction mixture was diluted with EtOAc, filteredthrough Celite, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (5 to 40% EtOAc in hexanes) to give tert-butyl3-(6,7-dihydro-3-(1H-indol-5-yl)-2-(2-methoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. ¹H NMR (400 MHz, CD₃OD) δ 7.35-7.40 (m, 1H), 7.26 (d,J=2.0 Hz, 1H), 7.24 (bs, 1H), 7.21-7.30 (m, 1H), 6.90 (d, J=8.4 Hz, 1H),6.87 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.35 (dd, J=0.8, 2.8 Hz,1H), 4.54 (dd, J=15.2, 21.6 Hz, 2H), 3.80-3.90 (m, 1H), 3.70-3.78 (m,1H), 3.69 (s, 3H), 2.82 (t, J=6.0 Hz, 2H), 1.91 (s, 3H), 1.40-1.50 (m,9H). MS: (ES) m/z calculated for C₂₇H_(31N4)O₃ [M+H]⁺ 459.23, found459.2.

Example 62 Synthesis of5-(5-tert-butyl-2-methylphenyl)-4,5,6,7-tetrahydro-3-(1H-indol-5-yl)-2-(2-methoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine

Step a: To a stirred solution of tert-butyl3-(6,7-dihydro-3-(1H-indol-5-yl)-2-(2-methoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(250 mg, 0.544 mmol) in anhydrous THF (4 mL) were added K₂CO₃ (150 mg,1.08 mmol) and trimethylacetyl chloride (163 mg, 1.36 mmol) at 0° C. Theresulting mixture was stirred for 16 h at room temperature. Aftercompletion of the reaction, the residue was dissolved in EtOAc/H₂O andwashed with brine and dried over MgSO₄. The solvent was removed underreduced pressure and the residue was purified by silica gel flashchromatography (0 to 20% EtOAc in hexanes) to give tert-butyl6,7-dihydro-2-(2-methoxy-6-methylphenyl)-3-(1-(pivaloyl)-1H-indol-5-yl)-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(220 mg). MS: (ES) m/z calculated for C₃₂H₃₉N₄O₄ [M+H]⁺ 542.2, found542.2.

Step b: To a solution of tert-butyl6,7-dihydro-2-(2-methoxy-6-methylphenyl)-3-(1-(pivaloyl)-1H-indol-5-yl)-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(220 mg, 0.405 mmol) in dichloromethane (5 mL) was added TFA (115 mg,1.01 mmol). The resulting mixture was stirred at room temperature for 2h. After completion of the reaction, the solvent was diluted with waterand aqueous NaHCO₃ and extracted with dichloromethane (2×50 mL) washedwith brine and dried over MgSO₄. The solvent was removed under reducedpressure and dried under vacuum to give1-(5-(4,5,6,7-tetrahydro-2-(2-methoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indol-1-yl)-2,2-dimethylpropan-1-one(125 mg). MS: (ES) m/z calculated for C₂₇H₃₁N₄O₂ [M+H]⁺ 443.24, found443.2.

Step c: To a mixed1-(5-(4,5,6,7-tetrahydro-2-(2-methoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridin-3-yl)-1H-indol-1-yl)-2,2-dimethylpropan-1-one(120 mg, 0.270 mmol), 4-tert-butyl-2-bromo-1-methylbenzene (93 mg, 0.406mmol), NaOtBu (52 mg, 2.2 mmol) and X-Phos (27 mg, 2.2 mmol) inp-dioxane (6 mL) was added Pd(OAc)₂ (6 mg, 0.027 mmol). The reactionmixture was degassed (N₂) for 5 min and stirred under N₂ at 105° C. for6 h. Upon completion the mixture was cooled down to room temperature,diluted with EtOAc (10 mL), filtered through Celite, washed with brineand dried over MgSO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (5 to 30%EtOAc in hexanes) and followed by prep HPLC to give5-(5-tert-butyl-2-methylphenyl)-4,5,6,7-tetrahydro-3-(1H-indol-5-yl)-2-(2-methoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine(12 mg). ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.48 (m, 2H), 7.20-7.35 (m, 5H),6.92-6.97 (m, 2H), 6.81 (d, J=8.0 Hz, 1H), 6.35 (d, J=3.2 Hz, 1H), 4.60(d, J=13.6 Hz, 1H), 4.44 (d, J=13.6 Hz, 1H), 3.75-3.85 (m, 2H), 3.72 (s,3H), 3.10-3.18 (m, 2H), 2.41 (s, 3H), 1.96 (s, 3H), 1.26 (s, 9H). MS:(ES) m/z calculated for C₃₃H₃₇N₄O [M+H]⁺ 505.2, found 505.2.

Example 63 Synthesis of5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine

Step a: To a solution of tert-butyl3-bromo-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(1.2 g, 3.6 mmol in dichloromethane (10 mL) was added TFA (1.47 g, 12.93mmol). The resulting mixture was stirred at room temperature for 2 h.Upon completion the mixture was diluted with water and aqueous NaHCO₃and extracted with dichloromethane, washed with brine, and dried overMgSO₄. The solvent was removed under reduced pressure and dried undervacuum to give3-bromo-2-(2-isobutoxy-6-methylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.(1.0 g) MS: (ES) m/z calculated for C₁₆H₂₂BrN₃ [M+H]⁺ 364.28, found364.2.

Step b: To a mixture of3-bromo-2-(2-isobutoxy-6-methylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(1.0 g, 2.58 mmol) in DMSO (5 mL) was added 3,5-dichloro-5-fluoropyridine (680 mg, 4.37 mmol), and Li₂CO₃ (610 mg, 12.3 mmol) at roomtemperature. The resulting mixture was stirred at 100° C. for 4 h. Aftercompletion of the reaction, it was cooled down to room temperature, thereaction mixture was diluted with EtOAc (20 mL), washed with brine anddried over MgSO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (5 to 20% EtOAcin hexanes) to afford3-bromo-5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine(0.8 g). MS: (ES) m/z calculated for C₂₂H₂₄BrCl₂N₄O [M+H]⁺ 509.04, found509.2.

Step c: To a suspension of3-bromo-5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine(600 mg, 1.4 mmol), 1H-indol-5-yl-5-boronic acid (550 mg, 1.8 mmol),Na₂CO₃ (500 mg, 3.6 mmol) in p-dioxane (6 mL) and water (1 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (300 mg, 0.37 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred under N₂ at100° C. for 2 h. The reaction mixture was diluted with EtOAc, filteredthrough Celite, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (5 to 20% EtOAc in hexanes) to give5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-3-(H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz,1H), 7.35 (d, J=8.0 Hz, 1H), 7.29 (bs, 1H), 7.20 (t, J=8.4 Hz, 1H), 6.92(t, J=7.2 Hz, 1H), 6.79-6.88 (m, 2H), 6.68-6.85 (m, 1H), 6.39 (d, J=3.1Hz, 1H), 4.40-4.55 (m, 1H), 4.20-4.40 (m, 1H), 3.82 (t, J=6.0 Hz, 2H),3.60-3.75 (m, 2H), 3.09-3.13 (m, 2H), 1.99 (m, 4H), 0.80-0.90 (m, 6H).MS: (ES) m/z calculated for C₃₀H₃₀Cl₂N₅O [M+H]⁺ 546.17, found 546.5

Example 64 Synthesis of5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-3-(1H-indol-6-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine

To a suspension of3-bromo-5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine(600 mg, 1.4 mmol), 1H-indol-6-yl-6-boronic acid (550 mg, 1.8 mmol), andNa₂CO₃ (500 mg, 3.6 mmol) in p-dioxane (6 mL) and water (1 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (300 mg, 0.37 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred under N₂ at 95°C. for 2 h. The reaction mixture was diluted with EtOAc, filteredthrough Celite, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (5 to 20% EtOAc in hexanes) to give5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-3-(1H-indol-6-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 8.14 (d, J=2.2 Hz, 1H), 7.81 (d, J=2.3 Hz,1H), 7.45 (d, J=1.6 Hz, 1H), 7.22-7.28 (m, 4H), 6.96 (dd, J=1.6, 8.6 Hz,1H), 6.87 (d, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 4.50 (dd, J=10.9,18.6 Hz, 2H), 3.78 (t, J=4.2 Hz, 2H), 3.66 (d, J=6.4 Hz, 2H), 3.06 (t,J=6.0 Hz, 2H), 1.99 (s, 3H), 1.83-1.90 (m, 1H), 0.85 (dd, J=3.5, 6.7 Hz,6H). MS: (ES) m/z calculated for C₃₀H₃₀Cl₂N₅O [M+H]⁺ 546.17, found546.1.

Example 65 Synthesis of3-chloro-5-[3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-1,2,4-thiadiazole

Step a: To a solution of3-bromo-2-(2-isobutoxy-6-methyl-phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine(363 mg, 1.0 mmol) and Et₃N (153 μL, 1.1 mmol) in THF (4 mL) was added3,5-dichloro-1,2,4-thiadiazole (171 mg. 1.1 mmol) in THF (2 mL) at roomtemperature. After 30 min, reaction mixture was diluted with CH₂Cl₂ (20mL) and washed with water (20 mL), dried over Na₂SO₄ and concentrated invacuo. The obtained residue was purified by silica gel flashchromatography (50% EtOAc in hexanes) to afford5-[3-bromo-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3-chloro-1,2,4-thiadiazole.MS: (ES) m/z calculated for C₁₉H₂₂BrCIN₅OS [M+H]⁺ 482.8, found 482.8.

Step b: To a solution of5-[3-bromo-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3-chloro-1,2,4-thiadiazole(471 mg, 0.977 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added1H-indol-5-ylboronic acid (157 mg, 0.977 mmol), Na₂CO₃ (155 mg, 1.465mmol) and degassed the resulting reaction mixture for a minute withnitrogen gas. Then was added Pd(dppf)Cl₂ complex with dichloromethane(80 mg, 0.0977 mmol), degassed the reaction mixture for another minutewith nitrogen gas and stirred at 50° C. overnight. The reaction mixturewas filtered through a small pad of Celite, washed with CH₂Cl₂ (15 mL),dried over Na₂SO₄ and concentrated in vacuo. The obtained residue waspurified by silica gel flash chromatography (75% EtOAc in hexanes) toget3-chloro-5-[3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-1,2,4-thiadiazole.

¹H NMR (400 MHz, Methanol-d₄) δ 7.45 (d, J=1.6 Hz, 1H), 7.32-7.20 (m,3H), 6.97 (dd, J=8.4, 1.7 Hz, 1H), 6.83 (dd, J=8.0, 24.5 Hz, 2H),6.41-6.35 (m, 1H), 4.77 (d, J=14.8 Hz, 1H), 4.68 (s, 1H), 4.03-3.97 (m,2H), 3.71-3.59 (m, 2H), 3.02 (t, J=6.0 Hz, 2H), 1.97 (s, 3H), 1.88 (dt,J=6.5, 13.2 Hz, 1H), 1.28 (s, 1H), 0.85 (dd, J=3.0, 6.7 Hz, 6H). MS:(ES) m/z calculated for C₂₇H₂₈ClN₆OS [M+H]⁺ 519.2, found 519.1.

Example 66 Synthesis of5-[3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3-isopropyl-1,2,4-thiadiazole

Step a: To a solution of3-chloro-5-[3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-1,2,4-thiadiazole(100 mg, 0.193 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54 μL, 0.977mmol), and Na₂CO₃ (155 mg, 1.465 mmol). The resulting reaction mixturewas degassed for a minute with nitrogen gas. Pd(dppf)Cl₂ complex withdichloromethane (80 mg, 0.0977 mmol) was then added and the mixturedegassed for another minute with nitrogen gas and stirred at 50° C.overnight. The reaction mixture was filtered through a small pad ofCelite, washed with CH₂Cl₂ (15 mL), dried over Na₂SO₄ and concentratedin vacuo. The obtained residue was purified by silica gel flashchromatography (75% EtOAc in hexanes) to get5-[3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3-isopropenyl-1,2,4-thiadiazole.MS: (ES) m/z calculated for C₃₀H₃₃N₆OS [M+H]⁺ 525.2, found 525.2.

Step b: To a solution of5-[3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3-isopropenyl-1,2,4-thiadiazole(50 mg, 0.095 mmol) in EtOAc (5 mL) was added 10% Pd/C (20 mg). Theresulting suspension was agitated under H₂ gas (40 psi) on Parr shakerat room temperature for 3 h. The reaction mixture was filtered through asmall pad of Celite, washed with EtOAc (15 mL), concentrated in vacuo.The obtained residue was purified by HPLC (CH₃CN/H₂O with 0.1% TFA) toafford5-[3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3-isopropyl-1,2,4-thiadiazole.¹H NMR (400 MHz, Methanol-d₄) δ 7.46 (dd, J=1.6, 0.7 Hz, 1H), 7.32-7.19(m, 3H), 6.97 (dd, J=8.5, 1.7 Hz, 1H), 6.89-6.76 (m, 2H), 6.38 (dd,J=0.9, 3.2 Hz, 1H), 4.76 (d, J=15.2 Hz, 1H), 4.67 (d, J=15.0 Hz, 1H),4.00 (t, J=5.9 Hz, 2H), 3.71-3.59 (m, 2H), 3.00 (td, J=2.8, 6.4, 6.9 Hz,3H), 1.97 (s, 3H), 1.88 (dt, J=6.5, 13.2 Hz, 1H), 1.27 (d, J=6.9 Hz,6H), 0.84 (dd, J=1.7, 6.5 Hz, 6H). MS: (ES) m/z calculated forC₃₀H₃₅N₆OS [M+H]⁺ 527.3, found 527.2.

Example 67 Synthesis of tert-butyl2-(2,6-dimethylphenyl)-3-(1H-indol-5-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate

Step a: To a mixture of tert-butyl3-amino-2-(2,6-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(485 mg, 1.41 mmol) and CuBr₂ (1.50 g, 6.7 mmol) in CH₃CN (30 mL) wasadded isopentyl nitrite (0.60 mL, 4.46 mmol) dropwise. After stirringfor 1 h, the mixture was quenched with water and extracted with EtOAc.The organic layer was separated, dried over Na₂SO₄, concentrated underreduced pressure and purified by silica gel flash chromatography (0 to35% EtOAc in hexanes) to afford tert-butyl3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₁₉H₂₅BrFN₃O₂[M+H]⁺ 406.1, found 406.1.

Step b: To a suspension of tert-butyl3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(35 mg, 0.086 mmol), indole-5-boronic acid (42 mg, 0.26 mmol) and K₂CO₃(36 mg, 0.26 mmol) in toluene (1.5 mL) and water (0.2 mL) was addedPd(PPh₃)₄(30 mg, 0.026 mmol). The reaction mixture was degassed (N₂) for2 min and stirred under N₂ at 110° C. for 3 h. The reaction mixture wascooled to room temperature, diluted with EtOAc, washed with brine anddried over Na₂SO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (0 to 45%EtOAc in hexanes) to afford tert-butyl2-(2,6-dimethylphenyl)-3-(1H-indol-5-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.¹H NMR (400 MHz, CDCl₃) δ 8.27 (br s, 1H), 7.39 (s, 1H), 7.18 (m, 2H),7.12 (dd, J=7.6, 7.6 Hz, 1H), 7.00 (d, J=7.6 Hz, 2H), 6.85 (dd, J=1.6,8.0 Hz, 1H), 6.44 (br s, 1H), 4.66 (br s, 2H), 3.82 (br s, 2H), 2.89 (t,J=5.8 Hz, 2H), 1.99 (s, 6H), 1.50 (s, 9H). MS: (ES) m/z calculated forC₂₇H₃₁N₄O₂ [M+H]⁺ 443.2, found 443.2.

Example 68 Synthesis of2-(2,6-dimethylphenyl)-3-(1H-indol-5-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride

Step a: tert-butyl2-(2,6-dimethylphenyl)-3-(1H-indol-5-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(81 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL) and chargedwith HCl in dioxane (4N, 2 mL). The resulting mixture was stirred atroom temperature for 1 h. The solvent was evaporated in vacuo to give2-(2,6-dimethylphenyl)-3-(1H-indol-5-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride.

Step b: A mixture of2-(2,6-dimethylphenyl)-3-(1H-indol-5-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (25 mg, 0.066 mmol), 2,2-dimethylpropanal (100 mg, 1.16mmol), NaBH(OAc)₃ (100 mg, 0.47 mmol), NEt₃ (0.015 mL, 0.11 mmol) andacetic acid (0.06 mL, 1 mmol) in DCM (1 mL) was stirred at 35° C. for 2h. After cooling to room temperature, the reaction mixture was dilutedwith EtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. Thesolvent was removed under reduced pressure and the residue was purifiedby reverse-phased preparative HPLC to afford2-(2,6-dimethylphenyl)-5-(2,2-dimethylpropyl)-3-(1H-indol-5-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.35 (br s, 1H), 7.35 (s, 1H), 7.19 (d, J=8.4,1H), 7.14 (m, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 2H), 6.83(dd, J=1.6, 8.8 Hz, 1H), 6.46 (m, 1H), 3.76 (br s, 2H), 2.93 (m, 4H),2.33 (br s, 2H), 1.98 (br s, 6H), 0.92 (br s, 9H). MS: (ES) m/zcalculated for C₂₇H₃₃N₄ [M+H]⁺ 413.2, found 413.2.

Example 69 Synthesis of2-(2,6-diethylphenyl)-3-(1H-indol-5-yl)-5-(2-(trifluoromethyl)benzyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of tert-butyl3-bromo-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(500 mg, 1.08 mmol), 1H-indol-5-ylboronic acid (900 mg, 5.59 mmol),K₂CO₃ (2.0 g, 14.5 mmol) in p-dioxane (10 mL) and water (2 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (200 mg, 0.24 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred under N₂ at100° C. for 2 h. The reaction mixture was diluted with EtOAc, filteredthrough Celite, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (5 to 30% EtOAc in hexanes) to give tert-butyl3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. MS: (ES) m/z calculated for C₃₀H₃₇N₄O₃ [M+H]⁺ 501.2,found 501.2.

The above tert-butyl3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylatewas dissolved in dichloromethane (5 mL) and charged with HCl in dioxane(4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the reaction was complete, the solvent was evaporated in vacuoto give3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₉N₄O [M+H]⁺ 401.2, found401.2.

Step b: NaBH(OAc)₃ (75 mg, 0.36 mmol) was added to a mixture of3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (30 mg, 0.07 mmol), 2-(trifluoromethyl)benzaldehyde (75mg, 0.42 mmol), and N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) indicholomethane (10 mL) under magnetic stirring. The resulting mixturewas stirred at 35° C. for 1 h. After cooling to room temperature, thereaction mixture was quenched with MeOH. The solvent was removed underreduced pressure and the residue was purified by HPLC (MeCN/H₂O, with0.1% TFA) to afford3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.62 (d,J=7.8 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.08-7.35(m, 4H), 6.95 (dt, J=1.3, 8.4 Hz, 1H), 6.44-6.77 (m, 3H), 3.92 (s, 2H),3.81 (d, J=13.5 Hz, 1H), 3.71 (d, J=13.5 Hz, 1H), 3.57 (m, 2H),2.82-2.91 (m, 4H), 2.04 (s, 3H), 1.92 (m, 1H), 0.83-0.88 (m, 6H). MS:(ES) m/z calculated C₃₃H₃₄F₃N₄O [M+H]⁺ 559.3, found 559.3.

Example 70 Synthesis of3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-5-(2-phenylpropan-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.11 mmol) in acetone (5 mL) under magneticstirring was added N,N-diisopropylethylamine (0.1 mL, 0.58 mmol),followed by acetone cyanohydrin (1 mL, 10.95 mmol). The resultingmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (10 to 75% EtOAc in hexanes) to give2-(3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-2-methylpropanenitrile.MS: (ES) m/z calculated for C₂₉H₃₄N₅O [M+H]⁺ 468.3, found 468.2.

Step b: The above2-(3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-2-methylpropanenitrile(25 mg, 0.05 mmol) was dissolved in THF (5 mL) and charged with asolution of phenylmagnesium bromide in THF (1 M, 1 mL, 1 mmol). Theresulting mixture was stirred at room temperature overnight and quenchedwith aqueous NH₄Cl solution. The reaction mixture was diluted withEtOAc, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and and the residue was purified by PreparativeTLC (45% EtOAc in hexanes) followed by HPLC (MeCN/H₂O, with 0.1% TFA) toafford3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-5-(2-phenylpropan-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.61-7.68 (m, 2H), 7.47 (d,J=0.9 Hz, 1H), 7.07-7.37 (m, 5H), 7.00 (dd, J=1.7, 8.5 Hz, 1H),6.63-6.76 (m, 2H), 6.48 (t, J=2.7 Hz, 1H), 3.91 (d, J=13.0 Hz, 1H), 3.82(d, J=13.0 Hz, 1H), 3.52-3.64 (m, 2H), 2.62-2.80 (m, 4H), 2.04 (s, 3H),1.93 (dq, J=6.8 Hz, 13.6, 1H), 1.45 (d, J=3.5 Hz, 6H), 0.86 (dd, J=3.5,6.8 Hz, 6H). MS: (ES) m/z calculated C₃₄H₃₉N₄O [M+H]⁺ 519.3, found519.3.

Example 71 Synthesis of3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-5-(1-(2-(trifluoromethyl)phenyl)ethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of tert-butyl3-bromo-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(1 g, 2.16 mmol) in dichloromethane (5 mL) was added a solution of HClin dioxane (4N, 5 mL). The resulting mixture was stirred at roomtemperature for 2 h. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (2 to 10%MeOH in dichloromethane with 1% NH₄OH) to give3-bromo-2-(2-isobutoxy-6-methylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.MS: (ES) m/z calculated for C₁₇H₂₃BrN₃O [M+H]⁺ 364.1, found 364.3.

The above3-bromo-2-(2-isobutoxy-6-methylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(100 mg, 0.27 mmol) was dissolved in DMF (5 mL) and charged with K₂CO₃(300 mg, 2.17 mmol) and 1-(1-bromoethyl)-2-(trifluoromethyl)benzene (100mg, 0.40 mmol). The reaction mixture was stirred under N₂ at 50° C. for14 h. The reaction mixture was diluted with EtOAc, washed with brine anddried over MgSO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (10 to 35% EtOAcin hexanes) to give3-bromo-2-(2-isobutoxy-6-methylphenyl)-5-(1-(2-(trifluoromethyl)phenyl)ethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.MS: (ES) m/z calculated for C₂₆H₃₀BrF₃N₃O [M+H]⁺ 536.1, found 536.4.

To a suspension of3-bromo-2-(2-isobutoxy-6-methylphenyl)-5-(1-(2-(trifluoromethyl)phenyl)ethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(50 mg, 0.09 mmol), 1H-indol-5-ylboronic acid (150 mg, 0.93 mmol), andK₂CO₃ (300 mg, 2.17 mmol) in p-dioxane (6 mL) and water (1 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (35 mg, 0.04 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred under N₂ at100° C. for 2 h. The reaction mixture was diluted with EtOAc, filteredthrough Celite, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified byPreparative TLC (50% EtOAc in hexanes) followed by HPLC (MeCN/H₂O, with1% TFA) to afford3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-5-(1-(2-(trifluoromethyl)phenyl)ethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridineas a mixture of rotamers. ¹H NMR (400 MHz, CDCl₃) δ 8.84 (m, 1H),8.20-8.45 (m, 1H) 7.40-7.75 (m, 3H) 7.14-7.35 (m, 5H), 6.44-6.77 (m,3H), 4.45-5.04 (m, 4H), 3.25-3.92 (m, 5H), 2.17 (s, 3H), 1.85 (m, 1H),1.28 (s, 3H), 0.83-0.88 (m, 6H). MS: (ES) m/z calculated C₃₄H₃₆F₃N₄O[M+H]⁺ 573.3, found 573.3.

Example 72 Synthesis of2-(2,6-diethylphenyl)-3-(1H-indol-5-yl)-5-(2-(trifluoromethyl)benzyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(500 mg, 1.2 mmol), 1H-indol-5-ylboronic acid (650 mg, 4.04 mmol), K₂CO₃(1.2 g, 8.8 mmol) in p-dioxane (8 mL) and water (1 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (200 mg, 0.24 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred under N₂ at100° C. for 2 h. The reaction mixture was diluted with EtOAc, filteredthrough Celite, washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (5 to 30% EtOAc in hexanes) to give tert-butyl2-(2,6-diethylphenyl)-3-(1H-indol-5-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₅N₄O₂ [M+H]⁺ 471.2, found 471.2.

The above tert-butyl2-(2,6-diethylphenyl)-3-(1H-indol-5-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate was dissolved in dichloromethane (5 mL) and chargedwith a solution of HCl in dioxane (4N, 5 mL). The resulting mixture wasstirred at room temperature for 2 h. After the reaction was complete,the solvent was evaporated in vacuo to give2-(2,6-diethylphenyl)-3-(1H-indol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₄H₂₇N₄[M+H]⁺ 371.2, found371.2.

Step b: NaBH(OAc)₃ (150 mg, 0.71 mmol) was added to a mixture of2-(2,6-diethylphenyl)-3-(1H-indol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (50 mg, 0.12 mmol), 2-(trifluoromethyl)benzaldehyde (100mg, 0.57 mmol), and N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) indicholomethane (10 mL) under magnetic stirring. The resulting mixturewas stirred at 35° C. for 1 h. After cooling to room temperature, thereaction mixture was quenched with MeOH. The solvent was removed underreduced pressure and the residue was purified by HPLC (MeCN/H₂O, with0.1% TFA) to afford3-(7-chloro-1H-indazol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.91-7.98 (m, 1H), 7.62 (dd,J=1.2, 7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.14-7.38 (m, 5H), 7.08 (d,J=7.6 Hz, 2H), 6.83 (dd, J=1.7, 8.5 Hz, 1H), 6.44 (m, 1H), 3.94 (s, 2H),3.79 (s, 2H), 2.84-2.95 (m, 4H), 2.21-2.39 (m, 4H), 1.04 (dt, J=0.7, 7.6Hz, 6H). MS: (ES) m/z calculated C₃₂H₃₂F₃N₄ [M+H]⁺ 529.3, found 529.3.

Example 73 Synthesis of2-(2,6-diethylphenyl)-3-(1H-indol-5-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: A mixture of3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinehydrochloride (700 mg, 1.89 mmol),2-chloro-5-(trifluoromethyl)pyrimidine (420 mg, 2.30 mmol) and TEA (1mL, 7.11 mmol) in CH₃CN (10 mL) was stirred at 80° C. for 1 h. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 40% EtOAc in hexanes) to afford3-bromo-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.MS: (ES) m/z calculated for C₂₁H₂₂BrF₃N₅[M+H]⁺ 480.1, found 480.1.

Step b: To a suspension of3-bromo-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(70 mg, 0.15 mmol), 1H-indol-5-ylboronic acid (70 mg, 0.43 mmol), andK₂CO₃ (240 mg, 1.72 mmol) in p-dioxane (6 mL) and water (1 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (50 mg, 0.06 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred under N₂ at100° C. for 1 h. The reaction mixture was cooled to room temperature,diluted with EtOAc, washed with brine, and dried over Na₂SO₄. Thesolvent was removed under reduced pressure and the residue was purifiedby preparative TLC (30% EtOAc in hexanes) followed by trituration inMeOH to give2-(2,6-diethylphenyl)-3-(1H-indol-5-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 2H), 8.20 (s, 1H), 7.43 (s, 1H),7.08-7.27 (m, 4H), 6.90 (dd, J=1.6, 8.8 Hz, 2H), 6.44-6.50 (m, 1H), 5.08(s, 2H), 4.35 (t, J=6.0 Hz, 2H), 3.00 (t, J=6.0 Hz, 2H), 2.16-2.40 (m,4H), 1.04 (t, J=7.2 Hz, 6H). MS: (ES) m/z calculated for C₂₉H₂₈F₃N₆[M+H]⁺ 517.2, found 517.3.

Example 74 Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-1H-benzo[d]imidazol-7-yl)methanol

Step a: A mixture of3-bromo-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(1.00 g, 2.08 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.32 g, 5.2mmol), K₂CO₃ (1.15 g, 8.3 mmol) and Pd(dppf)Cl₂ complex withdichloromethane (0.25 g, 0.3 mmol) in dioxane (12 mL) and water (0.7 mL)was stirred at 100° C. for 7 hours under nitrogen. It was then cooled toroom temperature, diluted with 20% MeOH/DCM and filtered through celite.The filtrate was collected, dried over Na₂SO₄, concentrated on a rotaryevaporator under reduced pressure. The residue was purified by silicagel flash chromatograph (0 to 100% EtOAc/hexanes) to give2-(2,6-diethylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.MS: (ES) m/z calculated for C₂₇H₃₃BF₃N₅O₂ [M+H]⁺ 527.6, found 527.6.

Step b: A mixture of2-(2,6-diethylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(0.400 g, 0.76 mmol), tert-butyl4-bromo-6-fluoro-7-(hydroxymethyl)-1H-benzo[d]imidazole-1-carboxylate(0.345 g, 1 mmol), K₂CO₃ (0.368 g, 2.66 mmol) and Pd(dppf)Cl₂ complexwith dichloromethane (0.15 g, 0.18 mmol) in dioxane (5 mL) and water(0.7 mL) was stirred at 100° C. for 3.5 hours under nitrogen. It wasthen cooled to room temperature, diluted with 20% MeOH/DCM and filteredthrough a plug of Na₂SO₄/celite. The filtrate was collected, dried overNa₂SO₄, concentrated on a rotary evaporator under reduced pressure. Theobtained crude was stirred with a mixture of TFA (1 mL) and DCM (5 mL)for 1.5 hours. The mixture was basicified with aq. NH₄OH, extracted withIPA/CHCl₃ and purified by silica gel flash chromatograph (0 to 100%EtOAc/hexanes), followed by reverse phase HPLC to yield(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-1H-benzo[d]imidazol-7-yl)methanol.¹H NMR (400 MHz, CDCl₃) δ 7.53 (br s, 2H), 7. 06 (s, 1H), 6.30 (m, 2H),6.10 (m, 2H), 5.46 (d, J=11.6, 1H), 4.00 (m, 4H), 3.41 (m, 2H), 2.05 (m,2H), 1.26 (m, 4H), 0.01 (br s, 6H). MS: (ES) m/z calculated forC₂₉H₂₇F₄N₇O [M+H]⁺ 565.2, found 565.2.

Example 75 Synthesis of3-(7-chloro-1H-pyrrolo[3,2-c]pyridin-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a solution of tert-butyl3-bromo-2-(2,6-diethylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(6.2 g, 14.3 mmol) in 56 mL of THF at −78° C. was added dropwise a 1.85M solution of nBuLi in hexanes (9.9 mL, 18.3 mmol). After stirring at−78° C. for 1 hr, trimethyl borate (5 mL, 44.3 mmol) was added and thesolution was warmed to room temperature and left stirring for 16 hrs.The reaction was quenched with 1 N HCl and the aqueous and organiclayers were separated. The aqueous layer was extracted with ethylacetate and the combined organic layers were dried with sodium sulfate,filtered and concentrated. The residue was purified by silica gel columnchromatography (80% ethyl acetate in hexanes) to yield(5-(tert-butoxycarbonyl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)boronicacid. MS: (ES) m/z calculated for C₂₁H₃₀BN₃O₄[M+H]⁺ 400.2, found 400.5.

Step b: To a solution of(5-(tert-butoxycarbonyl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)boronicacid (0.42 g, 1.1 mmol) and tert-butyl4-bromo-7-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.35 g, 1.1mmol) in 3.5 mL of dioxane was added a solution of potassium carbonate(0.58 g, 4.2 mmol) in 0.5 mL of H₂O followed by Pd(dppf)Cl₂ complex withdichloromethane (0.17 g, 0.2 mmol). The mixture was degassed with N₂ forfive minutes then heated at 100° C. for 16 hrs. The contents werefiltered and the filtrate was concentrated. The residue was purified bysilica gel column chromatography (40% ethyl acetate in hexanes) to givetert-butyl3-(7-chloro-1H-pyrrolo[3,2-c]pyridin-4-yl)-2-(2,6-diethylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(0.18 g, 0.35 mmol, 34%) and tert-butyl3-(1-(tert-butoxycarbonyl)-7-chloro-1H-pyrrolo[3,2-c]pyridin-4-yl)-2-(2,6-diethylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₃ClN₄O₂[M+H]⁺ 506.2, found 506.2 andMS: (ES) m/z calculated for C₃₃H₄₀ClN₅O₄[M+H]⁺ 606.3, found 606.2.

Step c: To a solution of tert-butyl3-(7-chloro-1H-pyrrolo[3,2-c]pyridin-4-yl)-2-(2,6-diethylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(0.18 g, 0.35 mmol) and tert-butyl3-(1-(tert-butoxycarbonyl)-7-chloro-1H-pyrrolo[3,2-c]pyridin-4-yl)-2-(2,6-diethylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(0.79 g, 0.13 mmol) in 2 mL of dioxane was added a solution of 4.0 M HClin dioxane (1 mL, 4 mmol). The solution was stirred at room temperaturefor 16 hrs and then heated to 50° C. for 2 hrs. The solvents wereremoved in vacuo and the residue was carried forward without furtherpurification.

The crude material,3-(7-chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride was re-dissolved in 2 mL of acetonitrile. To the solutionwas added Et₃N (0.27 mL, 1.9 mmol) followed by2-chloro-5-(trifluoromethyl)pyrimidine (0.11 g, 0.6 mmol). The mixturewas stirred as room temperature for 2 hrs then concentrated in vacuo.The residue was purified by silica gel column chromatography and theresultant solid was triturated with methanol to produce3-(7-chloro-1H-pyrrolo[3,2-c]pyridin-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.69 (s, 1H), 8.42 (s, 2H), 8.06 (s, 1H), 7.21(dd, J=2.7, 2.7 Hz, 1H), 7.12 (dd, J=7.7, 7.7 Hz, 1H), 6.94 (d, J=7.7Hz, 2H), 6.44 (dd, J=3.3, 2.0 Hz, 1H), 4.85 (s, 2H), 4.28 (t, J=5.9 Hz,2H), 2.97 (t, J=5.9 Hz, 2H), 2.34-2.16 (m, 4H) 0.95 (t, J=7.5 Hz, 6H).MS: (ES) m/z calculated for C₂₈H₂₅ClF₃N₇[M+H]⁺ 552.2, found 552.5.

Example 762-(2,6-diethylphenyl)-3-(3,6-difluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step a: To a solution of 4-bromo-6-fluoro-7-methoxyindoline-2,3-dione(0.2 g, 0.73 mmol) in 4.9 mL acetonitrile was added a solution of DAST(0.24 mL, 1.8 mmol) in 0.5 mL of dichloromethane. The solution washeated at 60° C. for 16 hrs and another portion of DAST (0.24 mL, 1.8mmol) was added and heating at 75° C. continued for another 24 hrs. Themixture was washed with water then the organic layer was dried withsodium sulfate, filtered and concentrated. The residue was purified onsilica gel column chromatography to afford4-bromo-3,3,6-trifluoro-7-methoxyindolin-2-one. MS: (ES) m/z calculatedfor C₉H₅BrF₃NO₂ [M+H]⁺ 296.0, found 296.2.

Step b: To a solution of 4-bromo-3,3,6-trifluoro-7-methoxyindolin-2-one(0.05 g, 0.17 mmol) in 0.9 mL of THF at 0° C. was added NaBH₄ (0.03 g,0.7 mmol) followed by BF₃ OEt₂ (0.16 mL, 1.3 mmol). The mixture wasstirred at room for 16 hrs then heated at 75° C. for 24 hrs. Thereaction was quenched with 1 N HCl then neutralized with NaOH. Theorganic and aqueous layers were separated and the aqueous layer wasextracted with dichloromethane. The combined organic layers were driedwith sodium sulfate, filtered and concentrated. The residue was purifiedby silica gel column chromatography to provide4-bromo-3,6-difluoro-7-methoxy-1H-indole.

Step c: To a solution of 4-bromo-3,6-difluoro-7-methoxy-1H-indole (0.03g, 0.12 mmol) in 1 mL of acetonitrile was added di-tert-butyldicarbonate (0.1 mL, 0.44 mmol) followed by DMAP (0.02 g, 13 mmol). Thesolution was stirred at room temperature for 30 min then concentrated invacuo. The residue was purified by silica gel column chromatography(100% hexanes) to give tert-butyl4-bromo-3,6-difluoro-7-methoxy-1H-indole-1-carboxylate.

Step d: To a solution of(5-(tert-butoxycarbonyl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)boronicacid (0.03 g, 0.08 mmol) and tert-butyl4-bromo-3,6-difluoro-7-methoxy-1H-indole-1-carboxylate (0.03 g, 0.08mmol) in 0.3 mL of dioxane was added a solution of potassium carbonate(0.03 g, 0.23 mmol) in 0.05 mL of H₂O followed by Pd(dppf)Cl₂ complexwith dichloromethane (0.02 g, 0.02 mmol). The mixture was degassed withN₂ for five minutes then heated at 100° C. for 2 hrs. The contents werefiltered and the filtrate was concentrated. The residue was purified bysilica gel column chromatography (40% ethyl acetate in hexanes) toprovide tert-butyl3-(1-(tert-butoxycarbonyl)-3,6-difluoro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₃₅H₄₂F₂N₄O₅[M+H]⁺ 637.3, found 637.6.

Step e: To a solution of tert-butyl3-(1-(tert-butoxycarbonyl)-3,6-difluoro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(0.027 g, 0.04 mmol) in 1 mL of dioxane was added a solution of 4.0 MHCl in dioxane (1 mL, 4 mmol). The solution was stirred at roomtemperature for 1 hr then heated at 50° C. for 16 hrs. The solvents wereremoved in vacuo and the residue was carried forward without furtherpurification.

The crude material,2-(2,6-diethylphenyl)-3-(3,6-difluoro-7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinewas re-dissolved in 0.5 mL of acetonitrile. To the solution was addedEt₃N (0.03 mL, 0.17 mmol) followed by2-chloro-5-(trifluoromethyl)pyrimidine (0.009 g, 0.05 mmol). The mixturewas stirred as room temperature for 2 hrs then concentrated in vacuo.The residue was purified by preparatory HPLC to yield2-(2,6-diethylphenyl)-3-(3,6-difluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(12 mg, 0.02 mmol, 49%). ¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1H), 7.94(s, 1H), 7.26-7.19 (m, 3H), 7.02 (d, J=2.1 Hz, 1H), 6.91 (d, J=7.1 Hz,1H), 6.40 (d, J=13.3 Hz, 1H), 4.89 (d, J=15.8 Hz, 1H), 4.80-4.65 (m,1H), 4.70 (d, J=15.8 Hz, 1H), 4.07 (d, J=2.8, 3H), 4.04-3.89 (m, 1H),3.08-2.93 (m, 2H), 2.61-2.50 (m, 2H), 2.23-2.14 (m, 1H), 1.99-1.89 (m,1H), 1.31 (t, J=7.5 Hz, 3H), 0.78 (t, J=7.5 Hz). MS: (ES) m/z calculatedfor C30H₂₇F₅N₆O [M+H]⁺ 583.2, found 583.5.

Example 77

The compounds in Table 1 and Table 2, below, were prepared using themethods described above. Characterization data (MS and/or NMR) isprovided for each compound listed.

TABLE 1 Structure & NMR/MS Characterization Data of Specific EmbodimentsStructure ¹H NMR MS

¹H NMR (400 MHz, CDCl₃) δ 9.29 (s, 1H), 8.48 (s, 2H), 7.07-7.37 (m, 2H),6.99-7.07 (m, 3H), 6.59 (dd, J = 0.9, 7.7, 1H), 6.50 (td, J = 1.3, 2.3,1H), 4.86 (br s, 2H), 4.37 (br s, 2H), 3.14 (d, J = 0.9, 6H), 3.05 (t, J= 5.9, 2H), 2.15-2.44 (m, 4H), 0.87-1.08 (m, 6H). MS: (ES) m/zcalculated C₃₂H₃₃F₃N₇O [M + H]⁺ 588.3, found 588.2.

¹H NMR (400 MHz, CDCl₃) δ 8.51 (br s, 1H), 8.07 (s, 2H), 7.28 (t, J =6.0, 1H), 7.19 (t, J = 7.6, 1H), 7.15 (m, 1H), 6.88 (dd, J = 6.4, 1.2,1H), 6.83 (d, J = 10, 1H), 6.45 (dd, J = 2.6, 2.6, 1H), 4.71 (d, J = 16,1H), 4.57 (d, J = 16, 1H), 4.34 (m, 1H), 4.28 (m, 1H), 4.15 (m, 1H),3.03 (dd, J = 5.8, 5.8, 2H), 2.50 (sextet, J = 7.2, 1H), 2.43 (sextet, J= 7.6, 1H), 2.16 (sextet, J = 7.5, 1H), 1.92 (sextet, J = 7.6, 1H), 1.29(d, J = 6.0, 6H), 1.21 (t, J = 7.6, 3H), 0.75 (t, J = 7.6, 3H). MS: (ES)m/z calculated for C₃₁H₃₂ClFN₆O [M + H]⁺ 559.2, found 559.2.

¹H NMR (400 MHz, d₆-DMSO) δ 8.69 (br s, 2H), 8.19 (s, 1H), 7.35 (d, J =8.0, 1H), 7.17 (t, J = 8.0, 1H), 7.06 (d, J = 8.0, 2H), 6.60 (d, J =8.0, 1H), 4.84 (s, 2H), 4.34 (t, J = 5.2, 2H), 2.94 (t, J = 5.2, 2H),1.88 (s, 6H). MS: (ES) m/z calculated for C₂₆H₂₂ClF₃N₇ [M + H]⁺ 524.2,found 524.2.

¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 8.11 (s, 2H), 7.17-7.30 (m, 2H),7.04 (d, J = 7.7, 2H), 6.36-6.47 (m, 2H), 4.72 (s, 2H), 4.26 (t, J =5.6, 2H), 4.05 (d, J = 2.5, 2H), 3.00 (t, J = 5.9, 2H), 2.10-2.36 (m,4H), 1.69 (m, 1H), 0.91 (m, 6H), 0.88 (m, 2H), 0.59 (m, 2H). MS: (ES)m/z calculated C₃₂H₃₄FN₆O [M + H]⁺ 537.3, found 537.2.

¹H NMR (400 MHz, d₆-DMSO) δ 13.5 (s, 1H), 8.27 (s, 1H), 7.97 (s, 1H),7.93 (dd, J = 1.6, 14, 1H), 7.25 (t, J = 8.4, 1H), 7.09 (d, J = 8.4,2H), 6.68 (d, J = 8.0, 1H), 6.48 (d, J = 8.0, 1H), 4.57 (s, 2H), 4.04(t, J = 5.2, 2H), 3.87 (s, 3H), 2.96 (t, J = 5.2, 2H), 2.02-2.26 (m,4H), 0.89 (t, J = 7.2, 6H). MS: (ES) m/z calculated for C₃₀H₂₉F₄N₆O [M +H]⁺ 565.2, found 565.2.

¹H NMR (400 MHz, CDCl₃) δ 8.47 (br s, 1H), 8.07 (s, 2H), 7.21 (t, J =7.6, 1H), 7.18 (dd, J = 2.8, 2.8, 1H), 7.04 (d, J = 7.6, 2H), 6.43 (dd,J = 2.4, 2.4, 1H), 6.40 (d, J = 13.6, 1H), 4.69 (s, 2H), 4.20-4.32 (m,3H), 4.04 (d, J = 2.8, 3H), 3.01 (t, J = 5.8, 2H), 2.12-2.40 (2 br s,4H), 1.29 (d, J = 6.0, 6H), 1.00 (br s, 6H). MS: (ES) m/z calculated forC₃₂H₃₅FN₆O₂ [M + H]⁺ 555.3, found 555.3.

¹H NMR (400 MHz, CDCl₃) δ 8.64 (br s, 1H), 8.13 (d, J = 1.2, 1H), 8.05(dd, J = 2.2, 1H), 7.82 (d, J = 2.8, 1H), 7.32 (dd, J = 2.8, 2.8, 1H),7.22 (d, J = 7.6, 1H), 7.03 (br d, J = 7.2, 2H), 6.98 (d, J = 8.0, 1H),6.56 (d, J = 7.6, 1H), 6.53 (dd, J = 2.8, 2.8, 1H), 4.56 (s, 2H), 4.15(t, J = 5.8, 2H), 3.07 (t, J = 5.8, 2H), 2.15-2.40 (2 br s, 4H), 0.99(br s, 6H). MS: (ES) m/z calculated for C₂₈H₂₇ClN₆ [M + H]⁺ 483.2, found483.2.

¹H NMR (400 MHz, CDCl₃) δ 8.58 (br s, 1H), 8.37 (s, 1H), 8.13 (d, J =1.2, 1H), 7.35 (dd, J = 5.8, 1H), 7.23 (t, J = 7.8, 1H), 7.04 (br d, J =6.4, 2H), 6.98 (d, J = 8.0, 1H), ), 6.56 (d, J = 7.6, 1H), ), 6.50 (dd,J = 2.6, 2.6, 1H), 4.66 (br s, 2H), 4.22 (t, J = 5.6, 2H), 3.09 (t, J =5.8, 2H), 2.15-2.40 (2 br s, 4H), 0.99 (br s, 6H). MS: (ES) m/zcalculated for C₂₉H₂₆ClF₃N₆ [M + H]⁺ 551.1, found 551.1.

¹H NMR (400 MHz, d₆-DMSO) δ 11.74 (s, 1H), 8.67 (br s, 2H), 7.54 (t, J =2.8, 1H), 7.13 (t, J = 7.6, 1H), 7.02 (d, J = 8.0, 2H), 6.46-6.54 (m,2H), 4.76 (br s, 2H), 4.30 (br s, 2H), 2.91 (t, J = 5.6), 1.88 (br s,6H). MS: (ES) m/z calculated for C₂₇H₂₃ClF₃N₆ [M + H]⁺ 523.2, found523.2.

¹H NMR (400 MHz, CDCl₃) δ 8.38 (br s, 1H), 8.11 (br s, 1H), 7.30 (dd, J= 13.2, 2.0, 1H), 7.10-7.18 (m, 2H), 6.97 (d, J = 7.6, 2H), 6.30-7.36(m, 2H), 4.55 (br s, 2H), 3.97 (m, 5H), 3.02 (t, J = 5.6, 2H), 2.18 (m,4H), 0.92 (br s, 6H). MS: (ES) m/z calculated for C₃₁H₂₈F₅N₅O [M + H]⁺582.2, found 582.2.

¹H NMR (400 MHz, CDCl₃) δ 8.43 (br s, 1H), 7.72 (s, 1H), 7.17 (m, 1H),7.11 (dd, J = 7.8, 7.8, 1H), 7.08 (m, 1H), 6.84 (dd, J = 13.6, 1.2, 1H),6.80 (dd, J = 7.6, 1.6, 1H), 6.74 (d, J =10, 1H), 6.41 (dd, J = 2.8,2.8, 1H), 4.41 (d, J = 15.2, 1H), 4.15 (d, J = 15.2, 1H), 3.75 (m, 2H),3.04 (dd, J = 5.6, 5.6, 2H), 2.45 (sextet, J = 7.2, 1H), 2.35 (sextet, J= 7.6, 1H), 2.08 (sextet, J = 7.6, 1H), 1.85 (sextet, J = 7.2, 1H), 1.73(m, 1H), 1.15 (t, J = 7.4, 3H), 0.84 (m, 2H), 0.67 (t, J = 7.6, 3H),0.52 (m, 2H). MS: (ES) m/z calculated for C₃₂H₃₀ClF₂N₅ [M + H]⁺ 558.1,found 558.2.

¹H NMR (400 MHz, CDCl₃) δ 8.45 (br s, 1H), 7.98 (s, 2H), 7.19 (t, J =2.8, 1H), 7.12 (t, J = 7.6, 1H), 6.94 (br d, J = 7.2, 2H), 6.85 (d, J =7.6, 1H), 6.46 (m, 2H), 4.61 (br s, 2H), 4.18 (m, 3H), 2.94 (t, J = 5.8,2H), 2.00-2.38 (2 br s, 4H), 1.20 (d, J = 6.0, 6H), 0.90 (br s, 6H). MS:(ES) m/z calculated for C₃₁H₃₃ClN₆O [M + H]⁺ 541.2, found 541.2.

¹H NMR (400 MHz, CDCl₃) δ 8.96 (br s, 1H), 8.10 (s, 2H), 7.22 (t, J =2.8, 1H), 7.17 (t, J = 7.8, 1H), 7.13 (m, 1H), 6.79 (d, J = 10, 1H),6.49 (d, J = 10, 1H), 6.37 (t, J = 5.2, 1H), 4.72 (m, 2H), 4.62 (m, 2H),4.44 (m, 1H), 4.12 (quint, J = 6.4, 1H), 3.10 (br s, 1H), 3.02 (t, J =5.8, 2H), 2.52 (sextet, J = 7.3, 1H), 2.42 (sextet, J = 7.6, 1H), 2.17(m, 1H), 1.95 (sextet, J = 7.6, 1H), 1.68 (m, 1H), 1.21 (t, J = 7.6,3H), 0.87 (m, 2H), 0.76 (t, J = 7.4, 3H), 0.55 (m, 2H). MS: (ES) m/zcalculated for C₃₂H₃₃FN₆O [M + H]⁺ 537.2, found 537.2.

¹H NMR (400 MHz, CDCl₃) δ 8.51 (br s, 1H), 7.11 (m, 1H), 7.05 (t, J =7.6, 1H), 6.86 (m, 3H), 6.79 (d, J = 8.4, 1H), 6.69 (d, J = 9.6, 1H),6.39 (d, J = 7.6, 1H), 6.35 (m, 1H), 4.40 (br s, 2H), 3.96 (m, 3H), 2.93(t, J = 5.8, 2H), 1.95- 2.30 (2 br s, 4H), 1.80-1.93 (m, 2H), 1.10 (t, J= 7.2, 2H), 0.83 (m, 6H). MS: (ES) m/z calculated for C₃₁H₃₁ClN₆ [M +H]⁺

¹H NMR (400 MHz, CDCl₃) δ 8.33 (br s, 1H), 7.78 (d, J = 1.6, 1H),7.08-7.16 (m, 2H), 7.05 (t, J = 7.6, 1H), 6.88 (br s, 2H), 6.78 (d, J =8.0, 1H), 6.40 (m, 2H), 4.13 (br s, 2H), 3.57 (t, J = 5.6, 2H), 3.00 (t,J = 5.6, 2H), 1.95-2.30 (2 br s, 4H), 1.65 b(m, 1H), 1.70- 1.00 (m, 8H),0.47 (m, 2H). MS: (ES) m/z calculated for C₃₂H₃₁Cl₂N₅ [M + H]⁺ 556.2,found 556.2.

¹H NMR (400 MHz, CDCl₃) δ 9.15 (br s, 1H), 8.18 (s, 1H), 7.38 (dd, J =13.2, 2.0, 1H), 7.26 (m, 1H), 7.22 (t, J = 7.6, 1H), 7.04 (br d, J =6.8, 2H), 6.46 (m, 1H), 6.37 (d, J = 11.2, 1H), 5.07 (d, J = 5.6, 2H),4.64 (br s, 2H), 4.07 (t, J = 5.6, 2H), 3.11 (t, J = 5.6, 2H), 2.10-2.40(2 br s, 4H), 2.00 (t, J = 5.6, 1H), 1.02 (br s, 6H). MS: (ES) m/zcalculated for C₃₁H₂₈F₅N₅O [M + H]⁺ 582.2, found 582.2.

¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 8.22 (d, J = 3.2, 1H), 7.66 (dd,J = 1.7, 14, 1H), 7.29 (t, J = 7.6, 1H), 7.12 (d, J = 7.6, 2H), 6.96(dd, J = 7.6, 10, 1H), 6.65 (dd, J = 4.4, 8.0, 1H), 4.71 (s, 2H), 4.15(t, J = 5.6, 2H), 3.04 (t, J = 5.6, 2H), 2.12-2.36 (m, 4H), 0.99 (t, J =7.6, 6H). MS: (ES) m/z calculated for C₂₉H₂₆F₅N₆ [M + H]⁺ 553.2, found553.2.

¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 1H), 7.64 (dd, J = 2.2, 14, 1H), 7.36(s, 1H), 7.33 (t, J = 8.4, 1H), 7.26 (d, J = 8.4, 1H), 7.21- 7.24 (m,1H), 7.16 (d, J = 7.6, 2H), 6.87 (dd, J = 1.6, 8.4, 1H), 6.36 (d, J =3.2, 1H), 4.10 (T, J = 6.0, 2H), 3.64 (s, 2H), 3.02 (t, J = 6.0, 2H),2.17-2.37 (m, 4H), 1.03 (t, J = 8.0, 6H). MS: (ES) m/z calculated forC₃₀H₂₈F₄N₅ [M + H]⁺ 534.2, found 534.2.

¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 7.65 (dd, J = 2.1, 14, 1H), 7.37(t, J = 7.6, 1H), 7.29 (d, J = 3.2, 1H), 7.18-7.23 (m, 3H), 6.57 (dd, J= 1.0, 12, 1H), 6.45 (t, J = 3.4, 1H), 4.10 (t, J = 5.6, 2H), 3.02 (t, J= 5.6, 2H), 2.18-2.39 (m, 4H), 1.04 (t, J = 7.6, 6H). MS: (ES) m/zcalculated for C₃₀H₂₇F₅N₅ [M + H]⁺ 552.2, found 552.2.

¹H NMR (400 MHz, CDCl₃) δ 8.56 (br s, 1H), 8.19 (s, 1H), 7.40 (dd, J =13.2, 2.0, 1H), 7.28 (t, J = 2.8, 1H), 7.24 (t, J = 7.2, 1H), 7.06 (d, J= 6.8, 2H), 6.53 (dd, J = 2.6, 2.6, 1H), 6.49 (d, J = 10.4, 1H), 4.63(br s, 2H), 4.07 (t, J = 5.6, 2H), 3.11 (t, J = 5.6, 2H), 2.05-2.40 (2br s, 4H), 1.02 (br s, 6H). MS: (ES) m/z calculated for C₃₀H₂₅ClF₅N₅[M + H]⁺ 586.2, found 586.2.

¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.91 (dd, J = 0.8, 2.2, 1H),7.19-7.30 (m, 2H), 7.00- 7.10 (m, 2H), 6.79 (dd, J = 2.8, 6.1, 1H), 6.61(d, J = 10.8, 1H), 6.43 (dd, J = 2.1, 3.2, 1H), 4.58 (d, J = 15.4, 1H),4.28 (d, J = 15.4, 1H), 3.82-3.92 (m, 2H), 3.15 (t, J = 5.7, 2H), 2.43(d, J = 0.9, 3H), 2.22 (s, 3H), 1.74 (s, 3H). MS: (ES) m/z calculatedC₂₈H₂₅ClF₂N₅ [M + H]⁺ 504.2, found 504.2.

¹H NMR (400 MHz, CDCl₃) δ 8.95 (br s, 1H), 7.80 (s, 1H), 7.22 (t, J =2.8, 1H), 7.10-7.20 (m, 3H), 6.86 (dd, J = 7.2, 1.6, 1H), 6.52 (t, J =10.4, 1H), 7.22 (dd, J = 2.8, 2.8 1H), 4.79 (m, 2H), 4.51 (d, J = 15.2,1H), 4.24 (d, J = 15.2, 1H), 3.84 (m, 2H), 3.12 (t, J = 6.2, 2H), 2.84(quint, J = 6.8, 1H), 2.62 (br s, 1H), 2.55 (sextet, J = 7.8, 1H), 2.45(sextet, J = 7.6, 1H), 2.20 (sextet, J = 7.4, 1H), 1.95 (sextet, J =7.4, 1H), 1.21 (m, 9H), 0.76 (t, J = 7.6, 3H). MS: (ES) m/z calculatedfor C₃₃H₃₅F₂N₅O [M + H]⁺ 556.3, found 556.3.

¹H NMR (400 MHz, CD₃OD) δ 8.23 (s, 2H), 7.37 (d, J = 3.2, 1H), 7.10 (d,J = 5.2, 2H), 6.83 (t, J = 4.0, 1H), 6.58 (d, J = 12, 1H), 6.34 (d, J =3.0, 1H), 4.81 (d, J = 17, 1H), 4.51 (d, J = 17, 1H), 4.13- 4.37 (m,2H), 2.97 (t, J = 5.6, 2H), 2.73-2.85 (m, 1H), 2.47 (s, 3H), 2.17 (s,3H), 1.70 (s, 3H), 1.23 (d, J = 6.8, 6H). MS: (ES) m/z calculated forC₃₀H₃₂FN₆ [M + H]⁺ 495.3, found 495.3.

¹H NMR (400 MHz, CDCl₃) δ 8.96 (br s, 1H), 8.18 (s, 2H), 7.23 (t, J =2.8, 1H), 7.23 (t, J = 2.8, 1H), 7.17 (t, J = 7.6, 1H), 7.13 (dd, J =7.6, 1.6, 1H), 6.86 (dd, J = 7.6, 1.2, 1H), 8.50 (d, J = 10.4, 1H), 6.38(t, J = 2.6, 1H), 4.74 (m, 2H), 4.64 (m, 2H), 4.46 (m, 1H), 4.47 (m,1H), 3.03 (m, 2H), 3.60-3.80 (m, 1H), 2.74 (quint, J = 6.8, 1H), 2.48(m, 2H), 2.19 (sextet, J = 7.4, 1H), 1.96 (sextet, J = 7.6, 1H), 1.21(m, 9H), 0.76 (t, J = 7.6, 3H). MS: (ES) m/z calculated for C₃₂H₃₅FN₆O[M + H]⁺ 539.3, found 539.3.

¹H NMR (400 MHz, CDCl₃) δ 9.07 (br s, 1H), 8.38 (s, 1H), 7.59 (dd, J =8.8, 2.8, 1H), 7.29 (t, J = 6.0, 1H), 7.19 (t, J = 7.6, 1H), 7.15 (dd, J= 8.0, 8.0, 1H), 6.87 (d, J = 7.6, 1H), 6.62 (m, 2H), 6.38 (t, J = 2.6,1H), 4.94 (s, 2H), 4.70 (d, J = 15.2, 1H), 4.40 (d, J = 15.6, 1H), 4.18(d, J = 5.6, 2H), ), 3.06 (dd, J = 5.6, 5.6, 2H), 2.52 (sextet, J = 7.6,1H), 2.43 (sextet, J = 7.4, 1H), 2.16 (sextet, J = 7.6, 1H), 1.94(sextet, J = 7.2, 1H), 1.22 (d, J = 11, 3H), 0.75 (d, J = 7.6, 3H). MS:(ES) m/z calculated for C₃₁H₂₉F₄N₅O [M + H]⁺ 564.2, found 564.2.

¹H NMR (400 MHz, CDCl₃) δ 8.17- 8.22 (m, 2H), 7.10-7.40 (m, 3H), 6.98(br, 2H), 6.39-6.54 (m, 2H), 4.62-4.68 (m, 2H), 4.08 (t, J = 5.7, 2H),3.13 (t, J = 5.8, 2H), 2.36 (J = 1.8, 3H), 2.00 (br, 6H). MS: (ES) m/zcalculated C₂₉H₂₅F₅N₅ [M + H]⁺ 538.2, found 538.2.

¹H NMR (400 MHz, CDCl₃) δ 8.85 (br s, 1H), 7.98 (s, 1H), 7.19 (d, J =12.8, 1H), 7.06 (m, 1H), 6.99 (t, J = 7.2, 1H), 6.95 (t, J = 6.8, 1H),6.67 (d, J = 7.2, 1H), 6.38 (d, J = 5.2, 1H), 6.20 (m, 1H), 4.72 (d, J =5.2, 2H), 4.55 (d, J = 15.6, 1H), 4.25 (d, J = 16.4, 1H), 3.87 (m, 2H),2.92 (dd, J = 5.6, 5.6, 2H), 2.33 (sextet, J = 7.4, 1H), 2.25 (sextet, J= 7.8, 1H), 2.09 (dd, J = 5.6, 5.6, 1H), 1.98 (sextet, J = 7.4, 1H),1.75 (sextet, J = 7.4, 1H), 1.02 (d, J = 7.6, 3H), 0.75 (d, J = 7.4,3H). MS: (ES) m/z calculated for C₃₁H₂₈F₅N₅O [M + H]⁺ 582.2, found582.2.

¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, J = 2.3, 1H), 7.54-7.58 (m, 2H),7.18-7.22 (m, 2H), 6.93- 7.00 (m, 2H), 6.90 (d, J = 9.6, 1H), 6.53 (d, J= 3.0, 1H), 4.67 (d, J = 15, 1H), 4.35 (d, J = 15, 1H), 4.07-4.15 (m,2H), 3.10 (t, J = 5.2, 2H), 2.84-2.94 (m, 1H), 2.25 (s, 3H), 1.78 (s,3H), 1.29 (d, J = 6.8, 6H). MS: (ES) m/z calculated for C₃₀H₃₀ClFN₅ [M +H]⁺ 514.2, found 514.2.

¹H NMR (400 MHz, CDCl₃) δ 8.33 (br s, 2H), 8.07 (br s, 1H), 7.13 (m,2H), 6.93 (t, J = 7.4, 1H), 6.81 (br s, 2H), 6.64 (d, J = 6.8, 1H), 6.43(d, J = 7.2, 1H), 6.36 (s, 1H), 4.71 (br s, 2H), 4.22 (br s, 2H), 2.90(t, J = 5.8, 1H), 2.30 (s, 3H), 1.85 (br s, 6H). MS: (ES) m/z calculatedfor C₂₈H₂₅F₃N₆ [M + H]⁺ 582.2, found 503.2.

¹H NMR (400 MHz, CDCl₃) δ 8.26 (br s, 1H), 8.18 (s, 1H), 7.37 (dd, J =13.6, 2.0, 1H), 7.24 (t, J = 2.8, 1H), 7.06 (t, J = 7.6, 1H), 6.94 (brs, 2H), 6.77 (d, J = 7.2, 1H), 6.57 (d, J = 7.2, 1H), 6.51 (m, 1H), 4.66(br s, 2H), 4.08 (t, J = 5.6, 2H), 3.13 (t, J = 5.8, 2H), 2.42 (s, 3H),2.00 (br s, 6H). MS: (ES) m/z calculated for C₂₉H₂₅F₄N₅ [M + H]⁺ 520.2,found 520.2.

¹H NMR (400 MHz, CDCl₃) δ 8.62 (br s, 1H), 8.16 (d, J = 5.2, 1H), 7.25(m, 1H), 7.20 (t, J = 7.8, 1H), 7.02 (d, J = 7.2, 2H), 6.94 (d, J = 8.0,1H), 6.59 (dd, J = 2.8, 2.8, 1H), 6.54 (d, J = 8.0, 1H), 6.36 (d, J =4.8, 1H), 4.80 (s, 2H), 4.31 (s, 2H), 3.02 (t, J = 5.8, 2H), 2.33 (s,3H), 2.10-2.40 (2 br s, 4H), 0.99 (br s, 6H). MS: (ES) m/z calculatedfor C₂₉H₂₉ClN₆ [M + H]⁺ 497.2, found 497.2.

¹H NMR (400 MHz, CDCl₃) δ 8.54 (br s, 1H), 8.09 (s, 2H), 7.29 (t, J =2.8, 1H), 7.06 (d, J = 4.8, 2H), 6.85 (d, J = 9.6, 1H), 6.80 (dd, J =4.4, 4.4, 1H), 6.47 (dd, J = 2.8, 2.8, 1H), 4.71 (d, J = 15.6, 1H), 4.57(d, J = 16, 1H), 4.35 (m, 1H), 4.11 (m, 1H), 2.79 (s, 3H), 3.04 (t, J =5.8, 2H), 2.20 (d, J = 1.6, 3H), 1.72 (s, 3H). MS: (ES) m/z calculatedfor C₂₇H₂₄ClFN₆O [M + H]⁺ 503.2, found 503.2.

¹H NMR (400 MHz, CDCl₃) δ 8.50 (br s, 1H), 8.09 (s, 2H), 7.30 (t, J =2.8, 1H), 7.08 (t, J = 7.6, 1H), 6.97 (d, J = 7.6, 1H), 6.95 (m, 2H),6.57 (m, 2H), 4.70 (s, 2H), 4.24 (br s, 2H), 3.79 (s, 3H), 3.03 (t, J =5.8, 2H), 1.98 (s, 6H). MS: (ES) m/z calculated for C₂₇H₂₅ClN₆O [M + H]⁺485.1, found 485.1.

¹H NMR (400 MHz, CDCl₃) δ 8.58 (br s, 1H), 8.04 (d, J = 5.6, 1H), 7.25(m, 1H), 7.21 (t, J = 7.6, 1H), 7.02 (d, J = 7.2, 2H), 6.94 (d, J = 8.0,1H), 6.56 (t, J = 2.4, 1H), 6.55 (d, J = 8.0, 1H), 5.97 (d, J = 5.2,1H), 4.80 (br s, 2H), 4.29 (br s, 2H), 3.88 (s, 3H), 3.02 (t, J = 5.8,2H), 2.15-2.42 (2 br s, 4H), 1.00 (s, 6H). MS: (ES) m/z calculated forC₂₉H₂₉ClN₆O [M + H]⁺ 513.2, found 513.2.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (br s, 1H), 8.08 (s, 2H), 7.25 (t, J =2.8, 1H), 7.06 (t, J = 7.6, 1H), 6.94 (br s, 2H), 6.76 (d, J = 7.2, 1H),6.56 (d, J = 7.2, 1H), 6.53 (dd, J = 2.6, 2.6, 1H), 4.71 (br s, 2H),4.23 (br s, 2H), 3.78 (s, 3H), 3.03 (t, J = 5.8, 2H), 2.43 (s, 3H), 1.99(br s, 6H). MS: (ES) m/z calculated for C₂₈H₂₈N₆O [M + H]⁺ 465.2, found465.2.

¹H NMR (400 MHz, CDCl₃) δ 8.19- 8.21 (m, 3H), 7.17-7.31 (m, 2H), 7.04(d, J = 7.7, 2H), 6.47 (dd, J = 2.0, 3.2, 1H), 6.40 (d, J = 10.9, 1H),4.74 (s, 2H), 4.28 (s, 2H), 3.02 (t, J = 5.8, 2H), 2.75 (h, J = 6.9,1H), 2.10-2.33 (m, 7H), 1.21 (d, J = 6.9, 6H), 0.80- 1.08 (m, 6H). MS:(ES) m/z calculated C₃₂H₃₆FN₆ [M + H]⁺ 523.3, found 523.3.

¹H NMR (TFA salt) (400 MHz, CD₃OD) δ 11.56 (br s, 1H), 8.30 (s, 1H),7.83 (dd, J = 9.6, 2.4, 1H), 7.44 (t, J = 2.8, 1H), 7.31 (t, J = 7.6,1H), 7.15 (br s, 2H), 7.10 (d, J = 8.8, 1H), 6.50 (m, 1H), 6.44 (m, 1H),4.69 (br s, 2H), 4.22 (br s, 2H), 3.05 (t, J = 5.8, 2H), 2.27 (br s,4H), 1.00 (br s, 6H). MS: (ES) m/z calculated for C₃₀H₂₆F₅N₅ [M + H]⁺552.2, found 552.2.

¹H NMR (400 MHz, CDCl₃) δ 9.01 (br s, 1H), 8.21 (s, 2H), 7.22 (t, J =7.6, 1H), 7.14 (t, J = 2.6, 1H), 7.05 (d, J = 7.6, 2H), 6.45 (m, 2H),4.74 (s, 2H), 4.24 (br s, 2H), 3.03 (t, J = 5.8, 2H), 2.76 (septet, J =7.0, 1H), 2.00-2.40 (2 br s, 4H), 1.21 (d, J = 7.2, 6H), 1.00 (br s,6H). MS: (ES) m/z calculated for C₃₁H₃₂F₂N₆ [M + H]⁺ 527.2, found 527.2.

¹H NMR (400 MHz, CD₃OD) δ 8.28 (s, 1H), 8.25 (s, 1H), 7.67 (dd, J = 2.2,14, 1H), 7.30 (t, J = 8.4, 1H), 7.24 (d, J = 8.0, 1H), 7.13 (d, J = 8.0,2H), 6.66 (d, J = 7.6, 1H), 4.72 (s, 2H), 4.16 (t, J = 5.6, 2H), 3.05(t, J = 5.6, 2H), 2.14-2.37 (m, 4H), 0.99 (t, J = 7.6, 6H). MS: (ES) m/zcalculated for C₂₉H₂₆ClF₄N₆ [M + H]⁺ 569.2, found 569.2.

¹H NMR (TFA salt) (400 MHz, CD₃OD) δ 8.71 (br s, 1H), 8.19 (s, 1H), 7.40(dd, J = 13.2, 2.0, 1H), 7.24 (t, J = 7.2, 1H), 7.20 (t, J = 2.8, 1H),), 7.06 (d, J = 6.8, 2H), 6.47 (m, 2H), 4.62 (br s, 2H), 4.07 (t, J =5.6, 2H), 3.11 (t, J = 5.6, 2H), 2.15-2.40 (2 br s, 4H), 1.00 (br s,6H). MS: (ES) m/z calculated for C₃₀H₂₅F₆N₅ [M + H]⁺ 570.2, found 570.2.

¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J = 3.0, 1H), 8.03 (s, 1H), 7.25-7.34 (m, 1H), 7.21 (t, J = 7.7, 1H), 6.96-7.04 (m, 3H), 6.52- 6.59 (m,2H), 4.76 (s, 2H), 4.25 (s, 2H), 3.97 (s, 3H), 3.02 (t, J = 5.9, 2H),2.10-2.38 (br, m, 4H), 0.88-1.08 (br, m, 6H). MS: (ES) m/z calculatedC₂₉H₂₉Cl₂N₆O [M + H]⁺ 547.2, found 547.1.

¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J = 9.7, 3H), 7.34 (t, J = 2.9, 1H),7.04-7.10 (m, 2H), 6.89 (d, J = 9.7, 1H), 6.78-6.85 (m, 1H), 6.43-6.46(m, 1H), 4.90 (d, J = 16.1, 1H), 4.68 (d, J = 16.1, 1H), 4.29-4.42 (m,2H), 3.06 (t, J = 5.9, 2H), 2.19 (d, J = 1.8, 3H), 1.73 (s, 3H). MS:(ES) m/z calculated C₂₇H₂₂ClF₄N₆ [M + H]⁺ 541.1, found 541.2.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J = 2.2, 2H), 7.38 (dd, J = 2.0,13.1, 1H), 7.18-7.34 (m, 2H), 7.04 (d, J = 7.7, 2H), 6.36-6.50 (m, 2H),4.64 (s, 2H), 4.07 (t, J = 5.8, 2H), 3.11 (t, J = 5.8, 2H), 2.10-2.40(m, 7H), 2.00 (br, 6H), 0.88-1.08 (m, 6H).. MS: (ES) m/z calculatedC₃₁H₂₉F₅N₅ [M + H]⁺ 566.2, found 566.2.

¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.18 (dt, J = 1.1, 2.1, 1H),7.18-7.47 (m, 2H), 7.07 (dd, J = 0.7, 4.5, 2H), 6.78-6.92 (m, 2H), 6.48(ddd, J = 0.6, 2.2, 3.1, 1H), 4.74 (d, J = 15.7, 1H), 4.44 (d, J = 15.7,1H), 3.99-4.14 (m, 2H), 3.13 (t, J = 5.8, 2H), 2.20 (d, J = 1.7, 3H),1.73 (s, 3H). MS: (ES) m/z calculated C₂₈H₂₂ClF₅N₅ [M + H]⁺ 558.1, found558.1.

¹H NMR (400 MHz, CDCl₃) δ 8.47 (br s, 1H), 8.09 (s, 2H), 7.31 (t, J =2.8, 1H), 7.20 (t, J = 7.6, 1H), 7.03 (d, J = 7.6, 2H), 6.95 (d, J =8.0, 1H), 6.56 (m, 2), 4.69 (br s, 2H), 4.24 (br s, 2H), 3.79 (s, 3H),3.02 (t, J = 5.8, 2H), 2.15-2.40 (m, 4H), 0.99 (br s, 6H). MS: (ES) m/zcalculated for C₂₉H₂₉ClN₆O [M + H]⁺ 513.2, found 513.2.

¹H NMR (TFA salt) (400 MHz, CD₃OD) δ 11.30 (br s, 1H), 7.56 (d, J = 6.8,1H), 7.46 (t, J = 2.8, 1H), 7.29 (t, J = 7.6, 1H), 7.13 (br s, 2H), 6.94(d, J = 7.6, 1H), 6.54 (d, J = 8.0, 1H), 6.50 (dd, J = 2.6, 1H), 6.10(d, J = 7.2, 1H), 4.71 (br s, 2H), 4.22 (br s, 2H), 3.08 (t, J = 5.8,2H), 2.30 (br s, 4H), 1.21 (d, J = 7.2, 6H), 1.00 (br s, 6H). MS: (ES)m/z calculated for C₂₈H₂₈ClN₇ [M + H]⁺ 498.2, found 498.2.

¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J = 2.4, 1H), 8.23 (s, 1H), 7.58 (dd,J = 2.5, 9.0, 1H), 7.24- 7.32 (m, 1H), 7.07 (t, J = 7.5, 1H), 6.95 (br,2H), 6.76-6.83 (m, 1H), 6.49-6.62 (m,3H), 4.58 (s, 2H), 4.20 (t, J =5.8, 2H), 3.06 (t, J = 5.8, 2H), 2.46 (s, 3H), 1.98 (br s, 6H). MS: (ES)m/z calculated C₂₉H₂₇F₃N₅ [M + H]⁺ 502.2, found 502.2.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 3H), 7.24-7.26 (m, 1H), 7.06 (t, J =7.5, 1H), 6.95 (br, 2H), 6.76 (dd, J = 1.0, 7.4, 1H), 6.50- 6.60 (m,2H), 4.75 (s, 2H), 4.28 (s, 2H), 3.03 (t, J = 5.9, 2H), 2.75 (p, J =6.9, 2H), 2.43 (s, 3H), 1.99 (br s, 6H), 1.21 (d, J = 6.9, 6H). MS: (ES)m/z calculated C₃₀H₃₃N₆ [M + H]⁺ 477.3, found 477.2.

¹H NMR (400 MHz, CDCl₃) δ 8.63 (br s, 1H), 8.19 (s, 2H), 7.25 (t, J =2.8, 1H), 7.19 (t, J = 7.6, 1H), 7.15 (dd, J = 7.6, 7.6, 1H), 6.88 (dd,J = 7.2, 0.8, 1H), 6.83 (d, J = 9.6, 1H), 6.44 (dd, J = 2.6, 1H), 4.75(d, J = 16, 1H), 4.63 (d, J = 16, 1H), 4.41 (quint, J = 6.6, 1H), 4.18(quint, J = 6.6, 1H), 3.03 (t, J = 5.8, 2H), 2.76 (sextet, J = 7.2, 1H),2.51 (sextet, J = 7.6, 1H), 2.41 (sextet, J = 8.0, 1H), 2.16 (sextet, J= 7.2, 1H), 1.93 (sextet, J = 7.6, 1H), 1.20 (m, 9H), 0.75 (t, J = 7.4,3H). MS: (ES) m/z calculated for C₃₁H₃₂ClFN₆ [M + H]⁺ 543.2, found543.2.

¹H NMR (400 MHz, CDCl₃) δ 8.56 (br s, 1H), 8.39 (s, 1H), 7.60 (dd, J =8.8, 2.4, 1H), 7.30 (t, J = 2.8, 1H), 7.20 (t, J = 7.6, 1H), 7.15 (t, J= 6.4, 1H), 6.88 (m, 2H), 6.64 (d, J = 8.8, 1H), 6.43 (t, J = 2.6, 1H),4.70 (d, J = 15.2, 1H), 4.42 (d, J = 15.6, 1H), 4.17 (t, J = 5.8, 2H),3.06 (t, J = 5.6, 2H), 2.50 (sextet, J = 8.0, 1H), 2.43 (sextet, J =7.8, 1H), 2.15 (sextet, J = 7.4, 1H), 1.92 (sextet, J = 7.6, 1H), 1.21(t, J = 7.4, 3H), 0.75 (t, J = 7.6, 3H). MS: (ES) m/z calculated forC₃₀H₂₆ClF₄N₅ [M + H]⁺ 568.2, found 568.2.

¹H NMR (400 MHz, CD₃OD) δ 7.92 (d, J = 2.5, 1H), 7.48 (dd, J = 2.6, 8.8,1H), 7.44 (d, J = 3.2, 1H), 7.27 (t, J = 7.6, 1H), 7.10 (br s, 2H), 6.92(d, J = 8.0, 1H), 6.80 (d, J = 8.8, 1H), 6.54 (d, J = 8.0, 1H), 6.51 (d,J = 3.1, 1H), 4.47 (br s, 2H), 4.04 (t, J = 5.6, 2H), 3.00 (t, J = 5.6,2H), 2.77-2.86 (m, 1H), 2.28 (br s, 4H), 1.21 (d, J = 6.8, 6H), 0.99 (brs, 6H). MS: (ES) m/z calculated for C₃₂H₃₅ClN₅ [M + H]⁺ 524.2, found524.2.

¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 7.60 (dd, J = 3.6, 1H), 7.31 (t,J = 2.6, 1H), 7.21 (t, J = 7.8, 1H), 7.03 (d, J = 7.2, 2H), 6.95 (d, J =8.0, 1H), 6.76 (d, J = 4.4, 1H), 6.61 (s, 1H), 6.54 (d, J = 8.0, 1H),4.86 (br s, 2H), 4.34 (br s, 2H), 3.04 (t, J = 6.0, 2H), 2.12- 2.42 (2br s, 4H), 0.99 (br s, 6H). MS: (ES) m/z calculated for C₂₉H₂₆ClF₃N₆[M + H]⁺ 551.2, found 551.2.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 2H), 8.13 (br s, 1H), 7.24 (t, J =2.8, 1H), 7.18 (t, J = 7.4, 1H), 7.14 (m, 1H), 6.87 (d, J = 7.6, 1H),6.59 (d, J = 11.2, 1H), 6.40 (t, J = 2.6, 1H), 4.76 (d, J = 16, 1H),4.62 (d, J = 16, 1H), 4.40 (quint, J = 6.6, 1H), 4.17 (quint, J = 6.8,1H), 3.03 (t, J = 5.6, 2H), 2.75 (sextet, J = 7.0, 1H), 2.53 (sextet, J= 7.6, 1H), 2.44 (sextet, J = 7.6, 1H), 2.41 (s, 3H), 2.19 (sextet, J =6.8, 1H), 1.96 (sextet, J = 7.6, 1H), 1.22 (m, 9H), 0.74 (t, J = 7.6,3H). MS: (ES) m/z calculated for C₃₂H₃₅FN₆ [M + H]⁺ 523.2, found 523.2.

¹H NMR (400 MHz, CDCl₃) δ 8.47 (br s, 2H), 8.23 (s, 1H), 7.26 (m, 1H),7.20 (t, J = 7.6, 1H), 7.02 (d, J = 5.6, 2H), 6.76 (d, J = 7.6, 1H),6.55 (d, J = 7.6, 1H) 6.49 (d, J = 2.8, 1H), 4.86 (s, 2H), 4.37 (s, 2H),3.04 (d, J = 6.0, 2H), 2.43 (s, 3H), 2.10-2.42 (2 br s, 4H), 1.00 (s,6H). MS: (ES) m/z calculated for C₃₀H₂₉F₃N₆ [M + H]⁺ 531.2, found 531.2.

¹H NMR (400 MHz, CDCl₃) δ 8.48 (br s, 2H), 8.19 (s, 1H), 7.25 (t, J =3.2, 1H), 7.19 (t, J = 7.6, 1H), 7.15 (dd, J = 8.0, 8.0, 1H), 6.88 (dd,J = 7.6, 1.2, 1H), 6.61 (d, J = 10.8, 1H), 6.38 (m, 1H), 4.92 (d, J =16, 1H), 4.69 (d, J = 16, 1H), 6.61 (quint, J = 6.4, 1H), 4.31 (quint, J= 6.6, 1H), 3.05 (t, J = 6.0, 2H), 2.50 (sextet, J = 7.6, 1H), 2.43(sextet, J = 7.6, 1H), 2.42 (s, 3H), 2.18 (sextet, J = 8.0, 1H), 1.96(sextet, J = 7.6, 1H), 1.21 (t, J = 7.6, 3H), 0.75 (t, J = 7.4, 3H). MS:(ES) m/z calculated for C₃₀H₂₈F₄N₆ [M + H]⁺ 549.2, found 549.2.

¹H NMR (400 MHz, CDCl₃) δ 8.36- 8.42 (m, 1H), 8.22 (s, 1H), 7.58 (dd, J= 2.5, 9.0, 1H), 7.16-7.32 (m, 2H), 7.03 (br, 2H), 6.78 (dd, J = 1.0,7.4, 1H), 6.49-6.62 (m, 3H), 4.58 (s, 2H), 4.21 (t, J = 5.9, 2H), 3.05(t, J = 5.9, 2H), 2.10- 2.45 (br m, 7H), 0.88-1.08 (br m, 6H). MS: (ES)m/z calculated C₃₁H₃₁F₃N₅ [M + H]⁺ 530.3, found 530.2.

¹H NMR (400 MHz, CDCl₃) δ 8.39 (q, J = 1.3, 1H), 8.17 (s, 1H), 7.59 (dd,J = 2.5, 9.1, 1H), 7.11-7.31 (m, 3H), 6.81-6.91 (m, 1H), 6.62 (d, J =10.2, 2H), 6.38 (dd, J = 2.1, 3.2, 1H), 4.69 (d, J = 15.4, 1H), 4.40 (d,J = 15.4, 1H), 4.13- 4.25 (m, 2H), 2.99-3.10 (m, 2H), 2.38-2.55 (m, 5H),1.90- 2.20 (m, 2H), 1.22 (t, J = 7.5, 3H), 0.74 (t, J = 7.5, 3H). MS:(ES) m/z calculated C₃₁H₃₀F₄N₅ [M + H]⁺ 548.2, found 548.2.

¹H NMR (TFA salt) (400 MHz, CD₃OD) δ 11.33 (br s, 1H), 8.22 (br s, 1H),7.65 (dd, J = 13.2, 2.0, 1H), 7.47 (t, J = 2.8, 1H), 7.23 (m, 2H), 6.95(d, J = 7.2, 1H), 6.85 (d, J = 10, 1H), 6.44 (dd, J = 2.4, 2.4, 1H),4.78 (d, J = 15.6, 1H), 4.41 (d, J = 16, 1H), 4.10 (m, 2H), 3.08 (t, J =5.6, 2H), 2.43 (m, 2.43, 2H), 2.14 (sextet, J = 7.5, 1H), 1.92 (sextet,J = 7.5, 1H), 1.23 (t, J = 7.4, 3H), 0.72 (t, J = 7.6, 3H). MS: (ES) m/zcalculated for C₃₀H₂₅ClF₅N₅ [M + H]⁺ 586.1, found 586.1.

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.82 (t, J = 1.6, 1H), 7.08-7.28 (m, 4H), 6.83-6.90 (m, 1H), 6.57 (d, J = 10.8, 1H), 6.40- 6.47(m,lH), 4.51 (d, J = 15.2, 1H), 4.24 (d, J = 15.2, 1H), 3.82- 3.85 (m,2H), 3.12 (t, J = 5.8, 2H), 2.84 (p, J = 6.9, 2H), 2.40-2.55 (m, 5H),1.95-2.21 (m, 2H), 1.20-1.25 (m, 9H), 0.73-0.79 (m, 3H). MS: (ES) m/zcalculated C₃₃H₃₆F₂N₅ [M + H]⁺ 540.3, found 540.2.

¹H NMR (400 MHz, CDCl₃) δ 8.24 (br s, 1H), 8.19 (s, 2H), 7.21 (t, J =3.0, 1H), 7.18 (d, J = 7.6, 1H), 7.02 (d, J = 7.2, 2H), 6.72 (d, J =7.2, 1H), 6.53 (d, J = 7.6, 1H), 6.50 (dd, J = 2.8, 2.8, 1H), 4.8 (br s,2H), 4.29 (br s, 2H), 3.02 (t, J = 5.6, 2H), 2.75 (septet, J = 7.0, 1H),2.38 (s, 3H), 2.00-2.40 (m, 4H), 1.21 (d, J = 7.2, 6H), 0.99 (br s, 6H).MS: (ES) m/z calculated for C₃₂H₃₆N₆ [M + H]⁺ 505.3, found 505.3.

¹H NMR (400 MHz, CDCl₃) δ 8.33 (br s, 1H), 8.33 (s, 1H), 7.14 (m, 1H),7.04 (t, J = 7.8, 1H), 6.86 (d, J = 7.2, 1H), 6.79 (d, J = 8.0, 1H),6.52 (t, J = 2.4, 1H), 6.39 (d, J = 7.6, 1H), 6.10 (s, 1H), 4.68 (br s,2H), 4.15 (t, J = 5.6, 2H), 2.82 (t, J = 5.8, 2H), 2.12 (s, 6H), 1.90-2.15 (m 4H), 0.82 (br s, 6H). MS: (ES) m/z calculated for C₃₀H₃₁ClN₆[M + H]⁺ 510.2, found 510.2.

¹H NMR (400 MHz, CDCl₃) δ 8.72 (br s, 1H), 8.20 (s, 2H), 7.24 (t, J =2.8, 2H), 7.07 (t, J = 7.6, 1H), 6.95 (d, J = 8.0, 2H), 6.57 (d, J =7.6, 1H), 6.54 (dd, J = 2.4, 2.4, 1H), 4.75 (s, 2H), 4.29 (br s, 2H),3.04 (t, J = 5.8, 2H), 2.76 (quint, J = 7.0, 1H), 1.97 (br s, 6H), 1.2(d, J = 7.2, 6H). MS: (ES) m/z calculated for C₂₉H₂₉ClN₆ [M + H]⁺ 497.2,found 497.2

¹H NMR (400 MHz, CD₃OD) δ 7.80 (s, 1H), 7.42 (d, J = 3.1, 1H), 7.33 (dd,J = 1.9, 14, 1H), 7.27 (t, J = 7.6, 1H), 7.11 (br s, 2H), 6.91 (d, 7.6,1H), 6.51-6.56, (m, 2H), 4.39 (br s, 2H), 3.85 (t, J = 5.6, 2H), 3.03(t, J = 5.6, 2H), 2.83- 2.93 (m, 1H), 2.30 (br s, 4H), 1.23 (d, J = 7.6,6H), 1.00 (br s, 6H). MS: (ES) m/z calculated for C₃₂H₃₄ClFN₅ [M + H]⁺542.2, found 542.2.

¹H NMR (400 MHz, CDCl₃) δ 8.72 (br s, 1H), 8.15 (s, 2H), 7.24 (t, J =3.0, 1H), 7.07 (t, J = 7.4, 1H), 6.95 (d, J = 8.0, 3H), 6.55 (d, J =2.8, 1H), 6.54 (d, J = 2.4, 1H), 4.73 (br s, 2H), 4.27 (br s, 2H), 3.03(t, J = 5.6, 2H), 2.10 (s, 3H), 1.97 (br s, 6H). MS: (ES) m/z calculatedfor C₂₇H₂₅ClN₆ [M + H]⁺ 469.1, found 469.1.

¹H NMR (400 MHz, CD₃OD- CDCl₃) δ 8.20 (br s, 2H), 7.52 (s, 1H), 7.34 (d,J = 3.2, 1H), 7.08 (t, J = 7.6, 1H), 6.95 (2 br s, 2H), 6.90 (d, J =8.0, 1H), 6.50 (d, J = 8.0, 1H), 6.45 (d, J = 3.2, 1H), 4.71 (br s, 2H),4.24 (br s, 2H), 2.97 (t, J = 5.8, 2H), 1.93 (br s, 6H). MS: (ES) m/zcalculated for C₂₆H₂₂Cl₂N₆ [M + H]⁺ 489.1, found 489.1.

¹H NMR (400 MHz, CDCl₃) δ 8.63 (br s, 1H), 8.15 (s, 2H), 7.24 (t, J =8.0, 1H), 7.20 (t, J = 7.6, 1H), 7.02 (d, J = 7.2, 2H), 6.93 (d, J =7.6, 1H), 6.54 (m, 2H), 4.73 (br s, 2H), 4.28 (br s, 2H), 3.02 (t, J =5.8, 2H), 2.07-2.42 (2 br s, 4H), 2.11 (s, 3H), 0.99 (br s, 6H). MS:(ES) m/z calculated for C₂₉H₂₉ClN₆ [M + H]⁺ 497.2, found 497.2.

¹H NMR (400 MHz, CDCl₃) δ 8.63 (br s, 1H), 7.24 (d, J = 4.8, 2H), 7.25(t, J = 2.8, 1H), 7.21 (d, J = 7.6, 1H), 7.03 (d, J = 7.2, 2H), 6.94 (d,J = 7.6, 2H), 6.54 (m, 2H), 6.47 (t, J = 4.6, 1H), 4.77 (br s, 2H), 4.32(br s, 2H), 3.04 (t, J = 5.8, 2H), 2.13-2.42 (2 br s, 4H), 0.99 (br s,6H). MS: (ES) m/z calculated for C₂₈H₂₇ClN₆ [M + H]⁺ 483.2, found 483.2.

¹H NMR (400 MHz, CDCl₃) δ 8.52 (br s, 1H), 8.19 (br s, 2H), 7.29 (t, J =2.8, 1H), 7.21 (t, J = 7.8, 1H), 7.03 (d, J = 7.6, 2H), 6.96 (d, J =8.0, 1H), 6.56 (d, J = 4.8, 1H), 6.55 (d, J = 2.6, 1H), 4.72 (br s, 2H),4.26 (br s, 2H), 3.02 (t, J = 5.8, 2H), 2.15-2.42 (2 br s, 4H), 0.99 (s,6H). MS: (ES) m/z calculated for C₂₈H₂₆ClFN₆ [M + H]⁺ 501.1, found501.1.

¹H NMR (400 MHz, CDCl₃) δ 8.49 (br s, 1H), 8.22 (s, 2H), 7.31 (t, J =2.6, 1H), 7.21 (t, J = 7.8, 1H), 7.03 (d, J = 7.5, 2H), 6.96 (d, J =8.0, 1H), 6.54 (m, 2H), 4.74 (br s, 2H), 4.27 (br s, 2H), 3.02 (t, J =11.6, 2H), 2.15-2.42 (2 br s, 4H), 0.99 (s, 6H). MS: (ES) m/z calculatedfor C₂₈H₂₆Cl₂N₆ [M + H]⁺ 517.2, found 517.2.

¹H NMR (400 MHz, CDCl₃) δ 8.47 (br s, 2H), 7.59 (s, 1H), 7.37 (d, J =3.2, 1H), 7.22 (t, J = 7.8, 1H), 7.04 (br d, J = 7.2, 2H), 6.89 (d, J =7.6, 1H), 6.49 (d, J = 7.6, 1H), 6.46 (d, J = 3.2, 1H), 4.82 (br s, 2H),4.36 (br s, 2H), 2.99 (t, J = 5.8, 2H), 2.22 (two br s, 4H), 0.98 (br s,6H). MS: (ES) m/z calculated for C₂₉H₂₆ClF₃N₆ [M + H]⁺ 551.2, found551.2.

¹H NMR (400 MHz, CDCl₃) δ 8.33 (br s, 1H), 8.61 (br s, 1H), 8.20 (s,2H), 7.26 (t, J = 2.8, 1H), 7.20 (t, J = 7.6, 1H), 7.03 (t, J = 7.2,2H), 7.60 (d, J = 7.6, 1H), 6.55 (m, 2H), 4.74 (br s, 2H), 4.29 (br s,2H), 3.03 (t, J = 5.85, 2H), 2.76 (septet, J = 7.0, 1H), 2.10-2.40 (2 brs, 4H), 1.21 (d, J = 7.2, 6H), 0.99 (br s, 6H). MS: (ES) m/z calculatedfor C₃₁H₃₃ClN₆ [M + H]⁺ 525.3, found 525.3.

¹H NMR (400 MHz, CD₃OD) δ 10.72 (s, 1H), 8.31 (s, 1H), 7.73 (dd, J =2.5, 9.1, 1H), 7.40 (d, J = 3.1, 1H), 7.25 (t, J = 7.6, 1H), 7.08 (s,2H), 6.90 (dd, J = 5.2, 8.3, 2H), 6.58 (d, J = 7.4, 1H), 6.45 (d, J =3.2, 1H), 4.83- 4.89 (m, 3H), 4.64 (s, 2H), 4.20 (s, 2H), 3.02 (t, J =5.8, 2H), 2.11- 2.46 (m, 4H), 0.85-1.08 (m, 6H). MS: (ES) m/z calculatedC₃₁H₃₁F₃N₅O [M + H]⁺ 564.2, found 564.2.

¹H NMR (400 MHz, CDCl₃) δ 8.80 (br s, 1H), 7.81 (s, 1H), 7.20 (t, J =7.6, 1H), 7.12 (t, J = 2.8, 1H), 7.02 (br d, J = 6.0, 2H), 6.91 (dd, J =13.6, 3.2, 1H), 6.64 (m, 1H), 6.52 (m, 2H), 4.41 (br s, 2H), 3.83 (t, J= 5.8, 2H), 3.11 (t, J = 5.8, 2H), 2.1-2.42 (2 br s, 4H), 1.81 (m, 1H),0.86-1.10 (m, 8H), 0.60 (m, 2H). MS: (ES) m/z calculated for C₃₂H₃₁F₂N₅[M + H]⁺ 524.3, found 524.3.

¹H NMR (400 MHz, CDCl₃) δ 8.61 (br s, 1H), 7.93 (d, J = 2.3, 1H), 7.27(d, J = 1.6, 1H), 7.20 (t, J = 7.6, 1H), 7.16 (t, J = 2.8, 1H), 7.02 (d,J = 6.8, 2H), 6.64 (m, 1H), 6.52 (m, 2H), 4.29 (br s, 2H), 3.72 (t, J =5.6, 2H), 3.16 (t, J = 5.6, 2H), 2.10-2.50 (2 br s, 4H), 1.79 (m, 1H),0.90-1.10 (m, 8H), 0.62 (m, 2H). MS: (ES) m/z calculated for C₃₂H₃₁ClFN₅[M + H]⁺ 540.2, found 540.2.

¹H NMR (400 MHz, CDCl₃) δ 8.79 (br s, 1H), 8.16 (s, 2H), 7.20 (t, J =7.8, 1H), 7.17 (t, J = 2.8, 1H), 7.02 (br d, J = 6.8, 2H), 6.64 (m, 1H),6.51 (m, 2H), 4.73 (br s, 2H), 4.28 (br s, 2H), 3.02 (t, J = 5.8, 2H),2.11 (s, 3H), 2.10-2.44 (2 br s, 4H), 0.99 (br s, 6H). MS: (ES) m/zcalculated for C₂₉H₂₉FN₆ [M + H]⁺ 482.2, found 482.2.

¹H NMR (400 MHz, CDCl₃) δ 8.65 (br s, 1H), 8.49 (br s, 2H), 7.23 (t, J =2.6, 1H), 7.20 (t, J = 7.6, 1H), 7.03 (br d, J = 7.6, 2H), 6.68 (m, 1H),6.51 (m, 2H), 4.84 (br s, 2H), 4.37 (br s, 2H), 3.05 (t, J = 12, 2H),2.04-2.42 (2 br s, 4H), 0.98 (br s, 6H). MS: (ES) m/z calculated forC₂₉H₂₆F₄N₆ [M + H]⁺ 535.2, found 535.2.

¹H NMR (400 MHz, CDCl₃) δ 8.60 (br s, 1H), 8.22 (s, 2H), 7.23 (t, J =6.8, 1H), 7.20 (d, J = 7.2, 1H), 7.02 (d, J = 6.8, 2H), 6.67 (m, 1H),6.52 (m, 2H), 4.74 (s, 2H), 4.27 (br s, 2H), 3.02 (d, J = 6.0, 2H),2.06-2.40 (two br s, 4H), 0.97 (br s, 6H). MS: (ES) m/z calculated forC₂₈H₂₆ClFN₆ [M + H]⁺ 501.2, found 501.2.

¹H NMR (400 MHz, CDCl₃) δ 8.75 (br s, 1H), 8.14 (d, J = 1.6, 1H), 8.06(m, 1H), 7.82 (d, J = 2.8, 1H), 7.25 (t, J = 2.8, 1H), 7.20 (d, J = 8.0,1H), 7.03 (br d, J = 7.6, 2H), 6.69 (m, 1H), 6.48-6.56 (m, 2H), 4.56 (brs, 2H), 4.15 (t, J = 5.8, 2H), 3.08 (t, J = 5.8, 2H), 2.00-2.42 (2 br s,4H), 0.99 (br s, 6H). MS: (ES) m/z calculated for C₂₈H₂₇FN₆ [M + H]⁺467.2, found 467.2.

¹H NMR (400 MHz, d₆-DMSO) δ 11.15 (s, 1H), 8.24 (d, J = 2.6, 1H), 8.05(d, J = 2.6, 1H), 7.31 (t, J = 2.8, 1H), 7.17 (t, J = 7.6, 1H), 7.13 (s,1H), 7.06 (d, J = 7.6, 2H), 6.62 (s, 1H), 6.34 (m, 1H), 4.39 (s, 2H),3.67 (t, J = 5.2, 2H), 2.97 (t, J = 6.0, 2H), 2.32 (s, 3H), 1.91 (s,6H). MS: (ES) m/z calculated for C₂₈H₂₆Cl₂N₅ [M + H]⁺ 514.2, found514.2.

¹H NMR (400 MHz, d₆-DMSO) δ 12.29 (s, 1H), 8.25 (d, J = 2.2, 1H), 8.24(d, J = 2.8, 1H), 7.49 (d, J = 8.8, 1H), 7.29 (s, 1H), 7.21 (t, J = 7.6,1H), 7.09 (d, J = 7.6, 2H), 7.05 (dd, J = 1.2, 8.4, 1H), 4.44 (s, 2H),2.99 (t, J = 6.0, 2H), 1.90 (s, 6H). MS: (ES) m/z calculated forC₂₈H₂₃Cl₂N₆ [M + H]⁺ 513.1, found 513.1.

¹H NMR (400 MHz, d₆-DMSO) δ 11.59 (s, 1H), 8.25 (d, J = 2.5, 1H), 8.06(d J = 2.2, 1H), 7.41 (t, J = 2.8, 1H), 7.33 (s, 1H), 7.20 (t, J = 7.2,1H), 7.10 (d, J = 7.2, 2H), 6.80 (d, J = 1.2, 1H), 6.49 (m, 1H), 4.41(s, 2H), 3.68 (t, J = 6.0, 2H), 2.98 (t, J = 6.0, 2H), 1.91 (s, 6H). MS:(ES) m/z calculated for C₂₇H₂₃Cl₃N₅ [M + H]⁺ 522.1, found 522.1.

¹H NMR (400 MHz, d₆-DMSO) δ 8.26 (d, J = 2.2, 1H), 8.07 (d, J = 2.2,1H), 8.05 (s, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.8, 1H), 7.21 (t, J =7.6, 1H), 7.10 (d, J = 7.6, 2H), 7.05 (dd, J = 1.6, 8.8, 1H), 4.43 (s,2H), 3.70 (t, J = 5.6, 2H), 3.01 (t, J = 5.6, 2H), 1.92 (s, 6H). MS:(ES) m/z calculated for C₂₆H₂₃Cl₂N₆ [M + H]⁺ 489.1, found 489.1.

¹H NMR (400 MHz, DMSO-d₆) δ 11.27 (s, 1H), 8.23 (d, J = 2.3, 1H), 8.07(d, J = 2.3, 1H), 7.11- 7.33 (m, 4H), 7.05 (d, J = 7.6, 2H), 6.35 (t, J= 2.4, 1H), 4.27 (s, 2H), 3.57 (t, J = 5.7, 1H), 3.01 (t, J = 5.7, 2H),1.95 (s, 6H). MS: (ES) m/z calculated C₂₇H₂₃Cl₂FN₅ [M + H]⁺ 506.1, found506.3.

¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 8.04 (dd, J = 0.4, 2.4, 1H),8.07 (d, J = 2.3, 1H), 7.62 (dd, J = 0.4, 2.3, 1H), 7.01-7.30 (m, 4H),6.73-6.84 (m, 2H), 6.42 (ddd, J = 0.9, 2.1, 3.1, 1H), 4.45 (d, J = 15.1,1H), 4.16 (d, J = 15.1, 1H), 3.71-3.83 (m, 2H), 3.15-3.23 (m, 2H), 2.25(s, 3H), 1.76 (s, 3H). MS: (ES) m/z calculated C₂₇H₂₃Cl₂FN₅ [M + H]⁺506.1, found 506.3.

¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 8.10 (dd, J = 0.8, 2.3, 1H),7.62 (dd, J = 0.8, 2.3, 1H), 7.05-7.20 (m, 4H), 6.93-7.02 (m, 3H),6.61-6.75 (m, 2H), 4.42 (s, 2H), 3.78 (t, J = 5.7, 2H), 3.17 (t, J =5.7, 2H), 2.05 (d, J = 3.3, 6H). MS: (ES) m/z calculated C₂₇H₂₃Cl₂FN₅[M + H]⁺ 506.1, found 506.3.

MS: (ES) m/z calculated C₂₈H₂₇F₃N₇ [M + H]⁺ 518.2, found 518.5.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 8.12 (d, J = 2.3, 1H), 7.63 (d,J = 2.3, 1H), 7.42-7.47 (m, 1H), 7.09-7.28 (m, 3H), 7.02 (d, J = 7.6,2H), 6.90 (dd, J = 8.5, 1.6, 1H), 6.50 (t, J = 2.5 Hz, 1H), 4.55 (s,2H), 3.81-3.69 (m, 2H), 3.16 (t, J = 5.8 Hz, 2H), 2.03 (s, 6H). MS: (ES)m/z calculated C₂₇H₂₄Cl₂N₅ [M + H]⁺ 488.1, found 488.3.

¹H NMR (400 MHz, Methanol-d₄) δ 7.73 (dd, J = 14.1, 2.0 Hz, 1H), 7.66(dd, J = 2.0, 0.6 Hz, 1H), 7.41-7.30 (m, 2H), 7.20 (dd, J = 8.3, 7.7 Hz,1H), 6.94 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 7.9 Hz, 2H), 6.71 (s, 1H),6.43 (dd, J = 3.1, 0.9 Hz, 1H), 4.94-4.65 (m, 2H), 4.03 (t, J = 5.7 Hz,2H), 3.95- 3.60 (m, 3H), 3.16-3.07 (m, 2H), 2.92 (p, J = 6.9 Hz, 1H),1.8 (brs, 3H), 1.24 (d, J = 6.9 Hz, 6H), 0.88 (s, 6H). MS: (ES) m/zcalculated for C₃₃H₃₇FN₅O [M + H]⁺ 538.3, found 538.3.

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.98 (d, J = 1.7, 1H), 7.54 (d,J = 8.4, 1H), 7.43 (dd, J = 0.8, 1.6, 1H), 7.09-7.32 (m, 4H), 6.92-6.99(m, 1H), 6.65- 6.78 (m, 2H), 6.46 (td, J = 1.1, 2.3, 1H), 3.89 (s, 2H),3.80 (d, J = 13.6, 1H), 3.70 (d, J = 13.6, 1H), 3.52-3.64 (m, 2H),2.79-2.98 (m, 4H), 2.05 (s, 3H), 0.85 (ddd, J = 0.8, 5.5, 6.6, 6H). MS:(ES) m/z calculated C₃₃H₃₃ClF₃N₄O [M + H]⁺ 593.2, found 593.3.

¹H NMR (400 MHz, Methanol-d₄) δ 8.25 (d, J = 1.9 Hz, 1H), 7.64 (dd, J =13.5, 2.1 Hz, 1H), 7.34 (dd, J = 1.7, 0.7 Hz, 1H), 7.28- 7.19 (m, 2H),7.04-6.95 (m, 2H), 6.93-6.76 (m, 2H), 4.85 (s, 2H), 4.18-4.01 (m, 2H),3.71- 3.58 (m, 2H), 3.02 (dd, J = 6.2, 2.3 Hz, 2H), 2.13 (s, 3H), 1.96(s, 3H), 1.87 (dt, J = 13.1, 6.6 Hz, 1H), 0.82 (dd, J = 6.7, 3.6 Hz,6H). MS: (ES) m/z calculated for C₃₂H₃₂F₄N5O [M + H]⁺ 578.3, found578.2.

¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 8.02 (s, 1H), 7.52 (d, J = 8.4,1H), 7.26 (s, 4H), 7.18 (dd, J = 2.3, 3.1, 1H), 7.08 (t, J = 7.9, 1H),6.97 (t, J = 7.7, 1H), 6.84 (s, 1H), 6.66 (s, 2H), 6.44 (s, 1H), 3.85(s, 2H), 3.40-3.70 (m, 4H), 2.90-3.05 (m, 4H), 2.35 (s, 3H), 1.92 (m,1H), 0.87 (m, 6H). MS: (ES) m/z calculated C₃₃H₃₃ClF₃N₄O [M + H]⁺ 593.2,found 593.3.

¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.44 (s, 1H), 7.07- 7.30 (m,3H), 6.96 (dt, J = 1.4, 8.5, 1H), 6.64-6.75 (m, 2H), 6.47 (dt, J = 1.4,3.2, 1H), 3.51- 3.82 (m, 4H), 3.25 (dtd, J = 3.3, 6.4, 9.8, 1H),2.75-3.01 (m, 4H), 2.54 (ddd, J = 3.4, 11.7, 15.0, 1H), 2.08-2.26 (m,1H), 1.84-2.07 (m, 4H), 1.23-1.33 (m, 3H), 0.79-0.96 (m, 6H). MS: (ES)m/z calculated C₂₉H₃₄F₃N₄O [M + H]⁺ 511.3, found 511.5.

¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.45 (dd, J = 1.0, 1.7, 1H),7.07-7.28 (m, 3H), 6.98 (dd, J = 1.6, 8.6, 1H), 6.64- 6.76 (m, 2H), 6.47(ddd, J = 0.9 2.0, 3.1, 1H), 3.67-3.77 (m, 2H), 3.51-3.63 (m, 2H),2.82-2.95 (m, 4H), 2.39 (dd, J = 8.9, 15.4, 1H), 2.02 (s, 3H), 1.91 (dt,J = 6.7, 13.3, 1H), 1.42 (tt, J = 7.2, 13.9, 2H), 0.94 (td, J = 1.6,7.4, 6H), 0.83 (dd, J = 3.9, 6.7, 6H). MS: (ES) m/z calculated C₃₀H₃₉N₄O[M + H]⁺ 471.3, found 471.5.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.33-7.43 (m, 2H); 7.14-7.31 (m,2H), 7.07 (d, J = 7.6, 2H), 6.83 (dd, J = 1.6, 8.5, 1H), 6.46 (ddd, J =1.0, 1.9, 3.1, 1H), 4.06 (dd, J = 4.1, 11.3, 2H), 3.82 (s, 2H),3.37-3.48 (m, 2H), 2.91-3.04 (m, 4H), 2.77 (ddd, J = 4.2, 7.8, 11.6,1H), 2.28 (ddq, J = 7.5, 15.0, 55.2, 4H), 1.89 (d, J = 11.3 Hz, 2H),1.75 (qd, J = 12.1, 4.3 Hz, 2H), 1.02 (td, J = 0.9, 7.6, 6H). MS: (ES)m/z calculated C₂₉H₃₅N₄O [M + H]⁺ 455.3, found 455.5.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.32-7.37 (m, 1H), 7.13-7.30 (m,3H), 7.06 (d, J = 7.7, 2H), 6.83 (dd, J = 1.6, 8.5, 1H), 6.46 (ddd, J =0.9, 2.1, 3.2, 1H), 3.72 (s, 2H), 2.96 (m, 4H), 2.82 (m, 1H), 2.34 (dq,J = 7.6, 15.1, 2H), 2.20 (dq, J = 15.2, 7.6 Hz, 2H), 1.99 (m, 2H), 1.50-1.72 (m, 6H), 0.93-1.06 (m, 6H). MS: (ES) m/z calculated C₂₉H₃₅N₄ [M +H]⁺ 439.3, found 439.2.

¹H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 7.38 (s, 1H), 7.02- 7.29 (m,5H), 6.85 (dt, J = 2.0, 8.6, 1H), 6.46 (dd, J = 1.9, 3.8, 1H), 3.84 (d,J = 12.9, 1H), 3.65 (d, J = 12.9, 1H), 2.75-3.05 (m, 4H), 2.11-2.48 (m,5H), 1.77- 1.87 (m, 1H), 1.18-1.35 (m, 3H), 0.80-1.17 (m, 12H). MS: (ES)m/z calculated C₂₉H₃₇N₄ [M + H]⁺ 441.3, found 441.2.

¹H NMR (400 MHz, CDCl₃) δ 8.26-8.32 (m, 1H), 7.38 (q, J = 0.9, 1H),7.11-7.30 (m, 3H), 7.06 (d, J = 7.7, 2H), 6.84 (dd, J = 1.6, 8.5, 1H),6.46 (ddd, J = 0.9, 2.0, 3.1, 1H), 3.77 (s, 2H), 2.89 (dq, J = 4.6, 9.2,4H), 2.15-2.47 (m, 5H), 1.58-1.75 (m, 2H), 1.45 (dp, J = 7.3, 14.4, 2H),0.80- 1.10 (m, 12H). MS: (ES) m/z calculated C₂₉H₃₇N₄ [M + H]⁺ 441.3,found 441.2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.46 (dd, J = 1.7, 0.7 Hz, 1H),7.33-7.19 (m, 3H), 6.98 (dd, J = 8.5, 1.7 Hz, 1H), 6.89-6.76 (m, 2H),6.38 (dd, J = 3.2, 0.9 Hz, 1H), 6.09 (dd, J = 2.2, 1.1 Hz, 1H), 5.41(dd, J = 2.2, 1.5 Hz, 1H), 4.80-4.64 (m, 2H), 4.04 (t, J = 5.9 Hz, 2H),3.70-3.58 (m, 2H), 3.01 (t, J = 6.0 Hz, 2H), 2.11 (t, J = 1.2 Hz, 3H),1.98 (s, 3H), 1.88 (dt, J = 13.1, 6.6 Hz, 1H), 1.31-1.14 (m, 1H), 0.83(dd, J = 6.8, 1.1 Hz, 6H). MS: (ES) m/z calculated for C₃₀H₃₃N₆OS [M +H]⁺ 525.2, found 525.2.

MS: (ES) m/z calculated for C₃₁H₃₁F₄N₆O [M + H]⁺ 579.2, found 579.2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.44 (dd, J = 2.2, 1.0 Hz, 1H),8.04-7.99 (m, 1H), 7.54-7.49 (m, 1H), 7.39-7.22 (m, 3H), 7.04-6.92 (m,2H), 6.90-6.82 (m, 1H), 6.41 (dd, J = 3.2, 0.8 Hz, 1H), 4.98-4.85 (m,1H), 4.79- 4.64 (m, 2H), 4.11-3.89 (m, 2H), 3.79-3.67 (m, 2H), 3.30 (p,J = 1.7 Hz, 8H), 3.16 (t, J = 5.7 Hz, 2H), 2.00 (s, 3H), 1.97-1.85 (m,1H), 0.85 (dd, J = 6.8, 1.2 Hz, 6H) MS: (ES) m/z calculated forC₃₁H₃₀ClF₃N₅O [M + H]⁺ 580.2, found 580.2.

¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 8.20 (q, J = 1.2, 1H), 8.09-8.16 (m, 1H), 7.31-7.44 (m, 2H), 7.13 (t, J = 8.0, 1H), 6.76- 6.83 (m,1H), 6.65-6.73 (m, 2H), 6.49-6.55 (m, 1H), 4.61- 4.79 (m, 2H), 4.06(ddt, J = 6.5, 13.2, 25.4, 2H), 3.51-3.67 (m, 2H), 3.05-3.14 (m, 2H),1.96 (s, 3H), 1.80-1.90 (m, 1H), 0.86- 0.77 (m, 6H). MS: (ES) m/zcalculated C₃₀H₂₉F₄N₆O [M + H]⁺ 565.2, found 565.5.

¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 8.21 (dd, J = 1.1, 2.2, 1H),7.33-7.48 (m, 1H), 7.11- 7.33 (m, 3H), 6.68-6.80 (m, 3H), 6.52 (qd, J =2.0, 3.3, 1H), 4.74-4.88 (m, 2H), 3.97-4.12 (m, 2H), 3.62 (dd, J = 1.0,6.4, 2H), 3.07 (t, J = 5.8, 2H), 2.01 (s, 3H), 1.91 (m, 1H), 0.82 (dd, J= 1.0, 6.7, 6H). MS: (ES) m/z calculated C₃₁H₂₉F₅N₅O [M + H]⁺ 582.2,found 582.5.

¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.90-7.97 (m, 1H), 7.58-7.65 (m,1H), 7.45-7.56 (m, 2H), 7.15-7.36 (m, 6H), 7.02 (dd, J = 1.7, 8.4, 1H),6.49 (ddd, J = 0.9, 2.0, 3.1, 1H), 3.92 (s, 2H), 3.73 (s, 2H), 2.97 (t,J = 5.6, 2H), 2.89 (t, J = 5.7, 2H). MS: (ES) m/z calculatedC₂₈H₂₂Cl₂F₃N₄ [M + H]⁺ 541.1, found 541.3.

¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.21-7.43 (m, 4H), 7.06-7.20 (m,4H), 6.85-6.95 (m, 2H), 3.84 (d, J = 17.3 Hz, 4H), 2.97 (s, 4H), 2.29(ddq, J = 7.5, 15.1, 54.9, 4H), 1.05 (td, J = 7.6, 0.7 Hz, 6H). MS: (ES)m/z calculated C₃₁H₃₀Cl₂FN₄ [M + H]⁺ 547.2, found 547.5.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.94 (d, J = 7.8, 1H), 7.59-7.66(m, 1H), 7.52 (t, J = 7.7, 1H), 7.08-7.39 (m, 5H), 6.97-7.04 (m, 2H),6.84 (dd, J = 1.6, 8.5, 1H), 6.43-6.49 (m, 1H), 3.94 (s, 2H), 3.78 (s,2H), 2.80-2.99 (m, 4H), 2.00 (s, 6H). MS: (ES) m/z calculated C₃₀H₂₈F₃N₄[M + H]⁺ 501.2, found 501.3.

¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.94 (d, J = 7.8, 1H), 7.60 (d,J = 7.9, 1H), 7.51 (t, J = 7.8, 1H), 7.21-7.35 (m, 2H), 7.16 (t, J =2.9, 1H), 7.07 (td, J = 0.9, 8.0, 1H), 6.97 (td, J = 1.0, 7.8, 1H), 6.85(br, 1H), 6.65 (br, 2H), 6.45 (br, 1H), 3.86 (s, 2H), 3.62-3.67 (m, 2H),3.50 (s, 2H), 3.01-2.83 (m,4H), 1.90 (m, 1H), 1.56 (s, 3H), 0.92-0.81(m, 6H). MS: (ES) m/z calculated C₃₃H₃₄F₃N₄O [M + H]⁺ 559.3, found559.3.

¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.46 (s, 1H), 7.38 (br, 4H),7.09-7.31 (m, 4H), 6.97 (d, J = 8.5, 1H), 6.66-6.76 (m, 2H), 6.42-6.49(m, 1H), 5.18 (s, 2H), 4.62-4.75 (m, 2H), 3.83-3.93 (m, 2H), 3.54-3.67(m, 2H), 2.90 (s, 2H), 2.03-1.86 (m, 4H), 0.79-0.92 (m, 6H). MS: (ES)m/z calculated C₃₃H₃₅N₄O₃ [M + H]⁺ 535.3, found 535.3.

¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.61-7.54 (m, 2H), 7.13-7.45 (m,5H), 7.07 (d, J = 7.7, 2H), 6.79-6.87 (m, 1H), 6.45 (dd, J = 2.1, 3.4,1H), 4.02 (s, 2H), 3.80 (s, 2H), 2.98 (t, J = 5.9, 2H), 2.86 (t, J =5.9, 2H), 2.42-2.14 (m, 4H), 0.93-1.06 (m, 6H). MS: (ES) m/z calculatedC₃₂H₃₁ClF₃N₄ [M + H]⁺ 563.2, found 563.5.

¹H NMR (400 MHz, CD₃OD) δ 7.80 (s, 1H), 7.42 (d, J = 3.4, 1H), 7.33 (dd,J = 2.1, 14, 1H), 7.14 (t, J = 7.6, 1H), 7.03 (br s, 2H), 6.93 (d, J =7.6, 1H), 6.54-6.58 (m, 2H), 4.40 (br s, 2H), 3.85 (t, J = 6.0, 2H),3.03 (t, J = 6.0, 2H), 2.82-2.92 (m, 1H), 1.95 (br s, 6H), 1.22 (d, J =7.2, 6H). MS: (ES) m/z calculated for C₃₀H₃₀ClFN₅ [M + H]⁺ 514.2, found514.2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.23 (dq, J = 2.1, 1.1 Hz, 1H),7.68-7.52 (m, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H),7.12 (dd, J = 8.3, 1.6 Hz, 1H), 6.87-6.76 (m, 2H), 4.90- 4.77 (m, 2H),4.17-3.99 (m, 3H), 3.62 (qd, J = 8.9, 6.2 Hz, 2H), 3.00 (t, J = 5.9 Hz,2H), 2.52 (s, 3H), 1.99 (s, 3H), 1.83 (dp, J = 13.2, 6.7 Hz, 1H), 1.23(t, J = 7.1 Hz, 1H), 0.89 (d, J = 6.7 Hz, 1H), 0.79 (dd, J = 6.8, 1.0Hz, 6H). MS: (ES) m/z calculated for C₃₁H₃₀F₄N₆O [M + H]⁺ 579.2, found579.2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.24 (dt, J = 2.0, 1.0 Hz, 1H),7.69-7.60 (m, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.11 (qd, J = 8.7, 1.2 Hz,2H), 6.88-6.78 (m, 2H), 4.84 (d, J = 1.5 Hz, 2H), 4.17- 3.99 (m, 2H),3.70-3.56 (m, 2H), 3.05-2.97 (m, 2H), 2.00 (d, J = 3.6 Hz, 3H), 1.85(dp, J = 13.3, 6.6 Hz, 1H), 0.80 (d, J = 6.7 Hz, 6H). MS: (ES) m/zcalculated for C₃₀H₃₀F₄N₇O [M + H]⁺ 580.2, found 580.2.

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.99 (s, 1H), 7.55 (d, J = 8.4,1H), 7.13-7.39 (m, 5H), 7.09 (d, J = 7.7, 2H), 6.83 (dd, J = 1.7, 8.5,1H), 6.42-6.49 (m, 1H), 3.90 (s, 2H), 3.79 (s, 2H), 2.86-3.00 (m, 4H),2.20-2.43 (m, 4H), 1.09-1.01 (m, 6H). MS: (ES) m/z calculatedC₃₂H₃₁ClF₃N₄ [M + H]⁺ 563.2, found 563.5.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.64 (d, J = 8.4, 1H), 7.12-7.31(m, 6H), 7.08 (d, J = 7.7 Hz, 2H), 6.84 (dd, J = 1.7, 8.5, 1H),6.42-6.49 (m, 1H), 3.83 (d, J = 12.5 Hz, 4H), 2.99- 2.90 (m, 4H),2.17-2.40 (m, 4H), 1.04 (td, J = 0.6, 7.6, 6H). MS: (ES) m/z calculatedC₃₁H₃₁Cl₂N₄ [M + H]⁺ 529.2, found 529.5.

¹H NMR (400 MHz, Methanol-d₄) δ 8.24 (dt, J = 2.0, 1.0 Hz, 1H), 7.60(dd, J = 13.5, 2.1 Hz, 1H), 7.47 (dd, J = 8.2, 0.7 Hz, 1H), 7.30-7.20(m, 3H), 6.95-6.78 (m, 3H), 6.41 (dd, J = 3.1, 0.9 Hz, 1H), 4.87 (d, J =4.5 Hz, 2H), 4.10 (dtd, J = 19.7, 13.5, 5.9 Hz, 2H), 3.69-3.58 (m, 2H),3.03 (t, J = 5.8 Hz, 2H), 2.00 (s, 3H), 1.84 (dp, J = 13.1, 6.6 Hz, 1H),0.79 (d, J = 6.7 Hz, 6H). MS: (ES) m/z calculated for C₃₁H₃₀F₄N₅O [M +H]⁺ 564.2, found 564.2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.20 (dd, J = 2.3, 1.2 Hz, 1H), 7.58(dd, J = 13.5, 2.1 Hz, 1H), 7.40-7.27 (m, 2H), 7.17 (t, J = 8.0 Hz, 1H),6.97-6.88 (m, 1H), 6.85-6.77 (m, 2H), 6.69 (d, J = 7.7 Hz, 1H),6.45-6.39 (m, 1H), 4.71 (d, J = 15.8 Hz, 1H), 4.20- 4.02 (m, 2H),3.69-3.63 (m, 2H), 3.06 (t, J = 5.9 Hz, 2H), 1.88 (s, 3H), 0.82 (d, J =6.9 Hz, 6H). MS: (ES) m/z calculated for C₃₁H₃₀F₄N₅O [M + H]⁺ 564.2,found 564.2.

¹H NMR (400 MHz, CD₃OD) δ 7.80 (s, 1H), 7.38 (d, J = 3.4, 1H), 7.33 (dd,J = 2.0, 14, 1H), 7.26 (t, J = 8.0, 1H), 7.10 (br s, 2H), 6.63 (dd, J =8.4, 11, 1 H), 6.49-6.53 (m, 2H), 4.38 (s, 2H), 3.85 (t, J = 6.0, 2H),3.03 (t, J = 6.0, 2H), 2.83-2.92 (m, 1H), 2.31 (br s, 4H), 1.22 (d, J =7.2, 6H), 0.99 (br s, 6H). MS: (ES) m/z calculated for C₃₂H₃₄F₂N₅ [M +H]⁺ 526.3, found 526.3.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.43-7.13 (m, 6H), 7.08 (d, J =7.7, 2H), 6.79-6.94 (m, 2H), 6.45 (ddd, J = 0.9, 2.0, 3.1, 1H), 3.83 (d,J = 16.1, 4H), 2.95 (t, J = 1.9, 4H), 2.11-2.45 (m, 4H), 1.32-1.21 (m,2H), 1.04 (t, J = 7.6 Hz, 6H). MS: (ES) m/z calculated C₃₁H₃₁ClFN₄ [M +H]⁺ 513.2, found 513.3.

¹H NMR (400 MHz, CDCl₃) δ 8.11-8.20 (m, 2H), 7.87 (s, 1H), 7.77 (d, J =8.0, 1H), 7.39-7.45 (m, 1H), 7.09-7.25 (m, 4H), 6.94 (dd, J = 1.6, 8.5,1H), 6.65- 6.77 (m, 2H), 6.45 (ddd, J = 0.9, 2.0, 3.0, 1H), 3.97 (s,2H), 3.80 (d, J = 13.4, 1H), 3.71 (d, J = 13.4, 1H), 3.52-3.65 (m, 2H),2.79- 2.99 (m, 4H), 2.04 (s, 3H), 1.82- 2.00 (m, 1H), 0.81-0.94 (m, 6H).MS: (ES) m/z calculated C₃₄H₃₃F₆N₄O [M + H]⁺ 627.3, found 627.3.

MS: (ES) m/z calculated for C₃₁H₃₀F₄N₅O [M + H] 564.2, found 564.2.

¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.44-7.51 (m, 1H), 7.08-7.20 (m,3H), 6.92 (dt, J = 1.1, 8.2, 1H), 6.71-6.78 (m, 1H), 6.67 (d, J = 8.2,1H), 6.48 (ddt, J = 0.8, 1.7, 3.0, 1H), 3.62- 3.83 (m, 2H), 3.50-3.62(m, 2H), 2.84-3.01 (m, 4H), 2.05 (s, 3H), 1.88 (dt, J = 6.9, 13.3, 1H),0.90 (s, 9H), 0.79-0.83 (m, 6H). MS: (ES) m/z calculated C₃₀H₃₉N₄O [M +H]⁺ 471.3, found 471.5.

¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.42 (dd, J = 0.8, 1.6, 1H),7.07-7.22 (m, 3H), 6.96 (dd, J = 1.6, 8.5, 1H), 6.64- 6.77 (m, 2H),6.43-6.50 (m, 1H), 3.78 (d, J = 13.7, 1H), 3.69 (d, J = 13.7, 1H),3.51-3.63 (m, 2H), 2.83-3.03 (m, 4H), 2.04 (s, 3H), 1.90 (dt, J = 6.6,13.3, 1H), 0.78-0.93 (m, 15H). MS: (ES) m/z calculated C₃₀H₃₉N₄O [M +H]⁺ 471.3, found 471.2.

TABLE 2 Structure & MS Characterization Data of Specific EmbodimentsStructure MS

MS: (ES) m/z calculated C₂₈H₂₇ClN₇ [M + H]⁺ 496.2, found 496.2.

MS: (ES) m/z calculated C₂₇H₂₂F₅N₇O [M + H]⁺ 541.2, found 541.1.

MS: (ES) m/z calculated for C₃₁H₃₀F₄N₅O [M + H]⁺ 564.2, found 564.2.

MS: (ES) m/z calculated C₃₀H₃₀FN₆O [M + H]⁺ 509.2 found 509.3.

MS: (ES) m/z calculated C₂₈H₂₅F₄N₆O [M + H]⁺ 537.2, found 537.4.

MS: (ES) m/z calculated C₂₈H₂₆ClF₃N₇ [M + H]⁺ 552.2, found 552.5.

MS: (ES) m/z calculated for C₃₁H₃₁F₄N₆O [M + H]⁺ 579.2, found 579.2.

MS: (ES) m/z calculated C₂₉H₂₉F₃N₇O [M + H]⁺ 548.2, found 548.3.

MS: (ES) m/z calculated C₂₈H₂₆ClF₃N₇ [M + H]⁺ 552.2, found 552.5.

MS: (ES) m/z calculated C₂₈H₂₇F₃N₇ [M + H]⁺ 518.2, found 518.3.

MS: (ES) m/z calculated C₂₈H₂₇F₃N₇ [M + H]⁺ 518.2, found 518.4.

MS: (ES) m/z calculated C₂₈H₂₇F₃N₇ [M + H]⁺ 518.2, found 518.5.

MS: (ES) m/z calculated C₂₉H₂₉F₃N₇O [M + H]⁺ 548.2, found 548.5.

MS: (ES) m/z calculated C₂₈H₂₆F₄N₇ [M + H]⁺ 536.2, found 536.5.

MS: (ES) m/z calculated C₂₇H₂₆F₃N₈ [M + H]⁺ 519.2, found 519.5.

MS: (ES) m/z calculated C₂₉H₂₉F₃N₇ [M + H]⁺ 532.2, found 532.5.

MS: (ES) m/z calculated C₂₈H₂₇F₃N₇ [M + H]⁺ 518.2, found 518.5.

MS: (ES) m/z calculated C₂₉H₂₆F₆N₇ [M + H]⁺ 586.2, found 586.5.

MS: (ES) m/z calculated C₂₉H₂₆F₅N₇O [M + H]⁺ 584.2, found 584.5.

MS: (ES) m/z calculated C₂₉H₂₉F₃N₇ [M + H]⁺ 532.2, found 532.5.

MS: (ES) m/z calculated C₂₉H₂₆ClF₄N₇O [M + H]⁺ 600.2, found 600.5.

MS: (ES) m/z calculated C₂₈H₂₇F₃N₇ [M + H]⁺ 518.2, found 518.5.

MS: (ES) m/z calculated C₃₁H₃₁F₄N₆O [M + H]⁺ 579.2, found 579.5.

MS: (ES) m/z calculated C₂₈H₂₆ClF₃N₇ [M + H]⁺ 552.2, found 552.5.

MS: (ES) m/z calculated C₂₇H₂₆F₃N₈ [M + H]⁺ 519.2, found 519.5.

MS: (ES) m/z calculated C₂₉H₂₉F₃N₇ [M + H]⁺ 532.2, found 532.5.

MS: (ES) m/z calculated C₃₀H₃₀F₄N₇O₂ [M + H]⁺ 596.2, found 596.5.

MS: (ES) m/z calculated C₂₈H₂₇F₃N₇ [M + H]⁺ 518.2, found 518.5.

MS: (ES) m/z calculated C₂₈H₂₇F₃N₇ [M + H]⁺ 518.2, found 518.5.

MS: (ES) m/z calculated C₃₀H₂₈ClF₄N₆O [M + H]⁺ 599.2, found 599.5.

MS: (ES) m/z calculated C₃₀H₂₇F₄N₆O₂ [M + H]⁺ 579.2, found 579.5.

MS: (ES) m/z calculated C₂₈H₂₅ClF₄N₇ [M + H]⁺ 570.2, found 570.4.

MS: (ES) m/z calculated C₂₉H₂₅ClF₃N₆O [M + H]⁺ 565.2, found 565.5.

MS: (ES) m/z calculated C₂₉H₂₈F₃N₆ [M + H]⁺ 517.2, found 517.3.

MS: (ES) m/z calculated C₂₉H₂₈ClF₃N₇ [M + H]⁺ 566.2, found 566.5.

MS: (ES) m/z calculated C₂₈H₂₆ClF₃N₇ [M + H]⁺ 552.2, found 552.5.

MS: (ES) m/z calculated C₂₉H₂₈F₄N₇O [M + H]⁺ 566.2, found 566.5.

MS: (ES) m/z calculated C₂₉H₂₈ClF₃N₇ [M + H]⁺ 566.2, found 566.5.

Example 78

This example illustrates the evaluation of the biological activityassociated with specific compounds of the invention.

Materials and Methods Cells C5a Receptor Expressing Cells U937 Cells

U937 cells are a monocytic cell line which express C5aR, and areavailable from ATCC (VA). These cells were cultured as a suspension inRPMI-1640 medium supplemented with 2 mM L-glutamine, 1.5 g/L sodiumbicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1 mM sodium pyruvate, and 10%FBS. Cells were grown under 5% CO₂/95% air, 100% humidity at 37° C. andsubcultured twice weekly at 1:6 (cells were cultured at a density rangeof 1×10⁵ to 2×10⁶ cells/mL) and harvested at 1×10⁶ cells/mL. Prior toassay, cells are treated overnight with 0.5 mM of cyclic AMP (Sigma, OH)and washed once prior to use. cAMP treated U937 cells can be used inC5aR ligand binding and functional assays.

Isolated Human Neutrophils

Optionally, human or murine neutrophils can be used to assay forcompound activity. Neutrophils may be isolated from fresh human bloodusing density separation and centrifugation. Briefly, whole blood isincubated with equal parts 3% dextran and allowed to separate for 45minutes. After separation, the top layer is layered on top of 15 mls ofFicoll (15 mls of Ficoll for every 30 mls of blood suspension) andcentrifuged for 30 minutes at 400×g with no brake. The pellet at thebottom of the tube is then isolated and resuspended into PharmLyse RBCLysis Buffer (BD Biosciences, San Jose, Calif.) after which the sampleis again centrifuged for 10 minutes at 400×g with brake. The remainingcell pellet is resuspended as appropriate and consists of isolatedneutrophils.

Assays Inhibition of C5aR Ligand Binding

cAMP treated U937 cells expressing C5aR were centrifuged and resuspendedin assay buffer (20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl₂, 5 mMMgCl₂, and with 0.1% bovine serum albumin) to a concentration of 3×10⁶cells/mL. Binding assays were set up as follows. 0.1 mL of cells wasadded to the assay plates containing 5 μL of the compound, giving afinal concentration of ˜2-10 μM each compound for screening (or part ofa dose response for compound IC₅₀ determinations). Then 0.1 mL of ¹²⁵Ilabeled C5a (obtained from Perkin Elmer Life Sciences, Boston, Mass.)diluted in assay buffer to a final concentration of ˜50 pM, yielding˜30,000 cpm per well, was added, the plates sealed and incubated forapproximately 3 hours at 4° C. on a shaker platform. Reactions wereaspirated onto GF/B glass filters pre-soaked in 0.3% polyethyleneimine(PEI) solution, on a vacuum cell harvester (Packard Instruments;Meriden, Conn.). Scintillation fluid (40 μl; Microscint 20, PackardInstruments) was added to each well, the plates were sealed andradioactivity measured in a Topcount scintillation counter (PackardInstruments). Control wells containing either diluent only (for totalcounts) or excess C5a (1 μg/mL, for non-specific binding) were used tocalculate the percent of total inhibition for compound. The computerprogram Prism from GraphPad, Inc. (San Diego, Ca) was used to calculateIC₅₀ values. IC₅₀ values are those concentrations required to reduce thebinding of radiolabeled C5a to the receptor by 50%. (For furtherdescriptions of ligand binding and other functional assays, seeDairaghi, et al., J. Biol. Chem. 274:21569-21574 (1999), Penfold, etal., Proc. Natl. Acad. Sci. USA. 96:9839-9844 (1999), and Dairaghi, etal., J. Biol. Chem. 272:28206-28209 (1997)).

Calcium Mobilization

Optionally, compounds may be further assayed for their ability toinhibit calcium flux in cells. To detect the release of intracellularstores of calcium, cells (e.g., cAMP stimulated U937 or neutrophils) areincubated with 3 μM of INDO-1AM dye (Molecular Probes; Eugene, Oreg.) incell media for 45 minutes at room temperature and washed with phosphatebuffered saline (PBS). After INDO-1AM loading, the cells are resuspendedin flux buffer (Hank's balanced salt solution (HBSS) and 1% FBS).Calcium mobilization is measured using a Photon Technology Internationalspectrophotometer (Photon Technology International; New Jersey) withexcitation at 350 nm and dual simultaneous recording of fluorescenceemission at 400 nm and 490 nm. Relative intracellular calcium levels areexpressed as the 400 nm/490 nm emission ratio. Experiments are performedat 37° C. with constant mixing in cuvettes each containing 10⁶ cells in2 mL of flux buffer. The chemokine ligands may be used over a range from1 to 100 nM. The emission ratio is plotted over time (typically 2-3minutes). Candidate ligand blocking compounds (up to 10 μM) are added at10 seconds, followed by chemokines at 60 seconds (i.e., C5a; R&DSystems; Minneapolis, Minn.) and control chemokine (i.e., SDF-1α; R&DSystems; Minneapolis, Minn.) at 150 seconds.

Chemotaxis Assays

Optionally, compounds may be further assayed for their ability toinhibit chemotaxis in cells. Chemotaxis assays are performed using 5 μmpore polycarbonate, polyvinylpyrrolidone-coated filters in 96-wellchemotaxis chambers (Neuroprobe; Gaithersburg, Md.) using chemotaxisbuffer (Hank's balanced salt solution (HBSS) and 1% FBS). C5aR ligands(i.e., C5a, R&D Systems; Minneapolis, Minn.) are use to evaluatecompound mediated inhibition of C5aR mediated migration. Otherchemokines (i.e., SDF-la; R&D Systems; Minneapolis, Minn.) are used asspecificity controls. The lower chamber is loaded with 29 μl ofchemokine (i.e., 0.03 nM C5a) and varying amounts of compound; the topchamber contains 100,000 U937 or neutrophil cells in 20 μl. The chambersare incubated 1.5 hours at 37° C., and the number of cells in the lowerchamber quantified either by direct cell counts in five high poweredfields per well or by the CyQuant assay (Molecular Probes), afluorescent dye method that measures nucleic acid content andmicroscopic observation.

Identification of Inhibitors of C5aR Assay

To evaluate small organic molecules that prevent the C5a receptor frombinding ligand, an assay was employed that detected radioactive ligand(i.e, C5a) binding to cells expressing C5aR on the cell surface (forexample, cAMP stimulated U937 cells or isolated human neutrophils). Forcompounds that inhibited binding, whether competitive or not, fewerradioactive counts are observed when compared to uninhibited controls.

Equal numbers of cells were added to each well in the plate. The cellswere then incubated with radiolabeled C5a. Unbound ligand was removed bywashing the cells, and bound ligand was determined by quantifyingradioactive counts. Cells that were incubated without any organiccompound gave total counts; non-specific binding was determined byincubating the cells with unlabeled ligand and labeled ligand. Percentinhibition was determined by the equation:

% inhibition=(1−[(sample cpm)−(nonspecific cpm)]/[(totalcpm)−(nonspecific cpm)])×100.

Dose Response Curves

To ascertain a candidate compound's affinity for C5aR as well as confirmits ability to inhibit ligand binding, inhibitory activity was titeredover a 1×10⁻¹⁰ to 1×10⁻⁴ M range of compound concentrations. In theassay, the amount of compound was varied; while cell number and ligandconcentration were held constant.

In Vivo Efficacy Models

The compounds of interest can be evaluated for potential efficacy intreating a C5a mediated conditions by determining the efficacy of thecompound in an animal model. In addition to the models described below,other suitable animal models for studying the compound of interest canbe found in Mizuno, M. et al., Expert Opin. Investig. Drugs (2005),14(7), 807-821, which is incorporated herein by reference in itsentirety.

Models of C5a Induced Leukopenia C5a Induced Leukopenia in a Human C5aRKnock-In Mouse Model

To study the efficacy of compounds of the instant invention in an animalmodel, a recombinant mouse can be created using standard techniques,wherein the genetic sequence coding for the mouse C5aR is replaced withsequence coding for the human C5aR, to create a hC5aR-KI mouse. In thismouse, administration of hC5a leads to upregulation of adhesionmolecules on blood vessel walls which bind blood leukocytes,sequestering them from the blood stream. Animals are administered 20ug/kg of hC5a and 1 minute later leukocytes are quantified in peripheralblood by standard techniques. Pretreatment of mice with varying doses ofthe present compounds can almost completely block the hC5a inducedleukopenia.

C5a Induced Leukopenia in a Cynomolgus Model

To study the efficacy of compounds of the instant invention in anon-human primate model model, C5a induced leucopenia is studied in acynomolgus model. In this model administration of hC5a leads toupregulation of adhesion molecules on blood vessel walls which bindblood leukocytes, hence sequestering them from the blood stream. Animalsare administered 10 ug/kg of hC5a and 1 minute later leukocytes arequantified in peripheral blood.

Mouse Model of ANCA Induced Vasculitis

On day 0 hC5aR-KI mice are intraveneously injected with 50 mg/kgpurified antibody to myeloperoxidase (Xiao et al, J. Clin. Invest. 110:955-963 (2002)). Mice are further dosed with oral daily doses ofcompounds of the invention or vehicle for seven days, then mice aresacrificed and kidneys collected for histological examination. Analysisof kidney sections can show significantly reduced number and severity ofcrescentic and necrotic lesions in the glomeruli when compared tovehicle treated animals.

Mouse Model of Choroidal Neovascularization

To study the efficacy of compounds of the instant invention in treatmentof age related macular degeneration (AMD) the bruch membrane in the eyesof hC5aR-KI mice are ruptured by laser photocoagulation (Nozika et al,PNAS 103: 2328-2333 (2006). Mice are treated with vehicle or a dailyoral or appropriate intra-vitreal dose of a compound of the inventionfor one to two weeks. Repair of laser induced damage andneovascularization are assessed by histology and angiography.

Rheumatoid Arthritis Models Rabbit Model of Destructive JointInflammation

To study the effects of candidate compounds on inhibiting theinflammatory response of rabbits to an intra-articular injection of thebacterial membrane component lipopolysaccharide (LPS), a rabbit model ofdestructive joint inflammation is used. This study design mimics thedestructive joint inflammation seen in arthritis. Intra-articularinjection of LPS causes an acute inflammatory response characterized bythe release of cytokines and chemokines, many of which have beenidentified in rheumatoid arthritic joints. Marked increases inleukocytes occur in synovial fluid and in synovium in response toelevation of these chemotactic mediators. Selective antagonists ofchemokine receptors have shown efficacy in this model (see Podolin, etal., J. Immunol. 169(11):6435-6444 (2002)).

A rabbit LPS study is conducted essentially as described in Podolin, etal. ibid., female New Zealand rabbits (approximately 2 kilograms) aretreated intra-articularly in one knee with LPS (10 ng) together witheither vehicle only (phosphate buffered saline with 1% DMSO) or withaddition of candidate compound (dose 1=50 μM or dose 2=100 μM) in atotal volume of 1.0 mL. Sixteen hours after the LPS injection, knees arelavaged and cells counts are performed. Beneficial effects of treatmentwere determined by histopathologic evaluation of synovial inflammation.Inflammation scores are used for the histopathologic evaluation:1—minimal, 2—mild, 3—moderate, 4—moderate-marked.

Evaluation of a Compound in a Rat Model of Collagen Induced Arthritis

A 17 day developing type II collagen arthritis study is conducted toevaluate the effects of a candidate compound on arthritis inducedclinical ankle swelling. Rat collagen arthritis is an experimental modelof polyarthritis that has been widely used for preclinical testing ofnumerous anti-arthritic agents (see Trentham, et al., J. Exp. Med.146(3):857-868 (1977), Bendele, et al., Toxicologic Pathol. 27:134-142(1999), Bendele, et al., Arthritis Rheum. 42:498-506 (1999)). Thehallmarks of this model are reliable onset and progression of robust,easily measurable polyarticular inflammation, marked cartilagedestruction in association with pannus formation and mild to moderatebone resorption and periosteal bone proliferation.

Female Lewis rats (approximately 0.2 kilograms) are anesthetized withisoflurane and injected with Freund's Incomplete Adjuvant containing 2mg/mL bovine type II collagen at the base of the tail and two sites onthe back on days 0 and 6 of this 17 day study. A candidate compound isdosed daily in a sub-cutaneous manner from day 0 till day 17 at aefficacious dose. Caliper measurements of the ankle joint diameter weretaken, and reducing joint swelling is taken as a measure of efficacy.

Rat Model of Sepsis

To study the effect of compounds of interest on inhibiting thegeneralized inflammatory response that is associated with a sepsis likedisease, the Cecal Ligation and Puncture (CLP) rat model of sepsis isused. A Rat CLP study is conducted essentially as described in FujimuraN, et al. (American Journal Respiratory Critical Care Medicine 2000;161: 440-446). Briefly described here, Wistar Albino Rats of both sexesweighing between 200-250 g are fasted for twelve hours prior toexperiments. Animals are kept on normal 12 hour light and dark cyclesand fed standard rat chow up until 12 hours prior to experiment. Thenanimals are split into four groups; (i) two sham operation groups and(ii) two CLP groups. Each of these two groups (i.e., (i) and (ii)) issplit into vehicle control group and test compound group. Sepsis isinduced by the CLP method. Under brief anesthesia a midline laparotomyis made using minimal dissection and the cecum is ligated just below theileocaecal valve with 3-0 silk, so the intestinal continuity ismaintained. The antimesinteric surface of the cecum is perforated withan 18 gauge needle at two locations 1 cm apart and the cecum is gentlysqueezed until fecal matter is extruded. The bowel is then returned tothe abdomen and the incision is closed. At the end of the operation, allrats are resuscitated with saline, 3 ml/100 g body weight, givensubcutaneously. Postoperatively, the rats are deprived of food, but havefree access to water for the next 16 hours until they are sacrificed.The sham operated groups are given a laparotomy and the cecum ismanipulated but not ligated or perforated. Beneficial effects oftreatment are measured by histopathological scoring of tissues andorgans as well as measurement of several key indicators of hepaticfunction, renal function, and lipid peroxidation. To test for hepaticfunction aspartate transaminase (AST) and alanine transaminase (ALT) aremeasured. Blood urea nitrogen and creatinine concentrations are studiedto assess renal function. Pro-inflammatory cytokines such as TNF-alphaand IL-1beta are also assayed by ELISA for serum levels.

Mouse SLE Model of Experimental Lupus Nephritis.

To study the effect of compounds of interest on a Systemic LupusErythematosus (SLE), the MRL/lpr murine SLE model is used. TheMRL/Mp-Tmfrsf6^(lpr/lpr) strain (MRL/lpr) is a commonly used mouse modelof human SLE. To test compounds efficacy in this model male MRL/lpr miceare equally divided between control and C5aR antagonists groups at 13weeks of age. Then over the next 6 weeks compound or vehicle isadministered to the animals via osmotic pumps to maintain coverage andminimize stress effects on the animals. Serum and urine samples arecollected bi-weekly during the six weeks of disease onset andprogression. In a minority of these mice glomerulosclerosis developsleading to the death of the animal from renal failure. Followingmortality as an indicator of renal failure is one of the measuredcriteria and successful treatment will usually result in a delay in theonset of sudden death among the test groups. In addition, the presenceand magnitude of renal disease may also be monitored continuously withblood urea nitrogen (BUN) and albuminuria measurements. Tissues andorgans were also harvested at 19 weeks and subjected to histopathologyand immunohistochemistry and scored based on tissue damage and cellularinfiltration.

Rat Model of COPD

Smoke induced airway inflammation in rodent models may be used to assessefficacy of compounds in Chronic Obstructive Pulmonary Disease (COPD).Selective antagonists of chemokines have shown efficacy in this model(see, Stevenson, et al., Am. J. Physiol Lung Cell Mol Physiol. 288L514-L522, (2005)). An acute rat model of COPD is conducted as describedby Stevenson et al. A compound of interest is administered eithersystemically via oral or IV dosing; or locally with nebulized compound.Male Sprague-Dawley rats (350-400 g) are placed in Perspex chambers andexposed to cigarette smoke drawn in via a pump (50 mL every 30 secondswith fresh air in between). Rats are exposed for a total period of 32minutes. Rats are sacrificed up to 7 days after initial exposure. Anybeneficial effects of treatment are assessed by a decrease inflammatorycell infiltrate, decreases in chemokine and cytokine levels.

In a chronic model, mice or rats are exposed to daily tobacco smokeexposures for up to 12 months. Compound is administered systemically viaonce daily oral dosing, or potentially locally via nebulized compound.In addition to the inflammation observed with the acute model (Stevensenet al.), animals may also exhibit other pathologies similar to that seenin human COPD such as emphysema (as indicated by increased mean linearintercept) as well as altered lung chemistry (see Martorana et al, Am.J. Respir. Crit Care Med. 172(7): 848-53.

Mouse EAE Model of Multiple Sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a model of humanmultiple sclerosis. Variations of the model have been published, and arewell known in the field. In a typical protocol, C57BL/6 (Charles RiverLaboratories) mice are used for the EAE model. Mice are immunized with200 ug myelin oligodendrocyte glycoprotein (MOG) 35-55 (PeptideInternational) emulsified in Complete Freund's Adjuvant (CFA) containing4 mg/ml Mycobacterium tuberculosis (Sigma-Aldrich) s.c. on day 0. Inaddition, on day 0 and day 2 animals are given 200 ng of pertussis toxin(Calbiochem) i.v. Clinical scoring is based on a scale of 0-5: 0, nosigns of disease; 1, flaccid tail; 2, hind limb weakness; 3, hind limbparalysis; 4, forelimb weakness or paralysis; 5, moribund. Dosing of thecompounds of interest to be assessed can be initiated on day 0(prophylactic) or day 7 (therapeutic, when histological evidence ofdisease is present but few animals are presenting clinical signs) anddosed once or more per day at concentrations appropriate for theiractivity and pharmacokinetic properties, e.g. 100 mg/kg s.c. Efficacy ofcompounds can be assessed by comparisons of severity (maximum meanclinical score in presence of compound compared to vehicle), or bymeasuring a decrease in the number of macrophages (F_(4/80) positive)isolated from spinal cords. Spinal cord mononuclear cells can beisolated via discontinuous Percoll-gradient. Cells can be stained usingrat anti-mouse F_(4/80)-PE or rat IgG2b-PE (Caltag Laboratories) andquantitated by FACS analysis using 10 ul of Polybeads per sample(Polysciences).

Mouse Model of Kidney Transplantation

Transplantation models can be performed in mice, for instance a model ofallogenic kidney transplant from C57BL/6 to BALB/c mice is described inFaikah Gueler et al, JASN Express, Aug. 27, 2008. Briefly, mice areanesthetized and the left donor kidney attached to a cuff of the aortaand the renal vein with a small caval cuff, and the ureters removed enblock. After left nephrectomy of the recipient, the vascular cuffs areanastomosed to the recipient abdominal aorta and vena cava,respectively, below the level of the native renal vessels. The ureter isdirectly anastomosed into the bladder. Cold ischemia time is 60 min, andwarm ischemia time is 30 min. The right native kidney can be removed atthe time of allograft transplantation or at posttransplantation day 4for long-term survival studies. General physical condition of the miceis monitored for evidence of rejection. Compound treatment of animalscan be started before surgery or immediately after transplantation, egby sub cut injection once daily. Mice are studied for renal function andsurvival. Serum creatinine levels are measured by an automated method(Beckman Analyzer, Krefeld, Germany).

Mouse Model of Ischemia/Reperfusion

A mouse model of ischemia/reperfusion injury can be performed asdescribed by Xiufen Zheng et al, Am. J. Pathol, Vol 173:4, October,2008. Briefly, CD1 mice aged 6-8 weeks are anesthetized and placed on aheating pad to maintain warmth during surgery. Following abdominalincisions, renal pedicles are bluntly dissected and a microvascularclamp placed on the left renal pedicle for 25-30 minutes. Followingischemia the clamps are removed along with the right kidney, incisionssutured, and the animals allowed to recover. Blood is collected forserum creatinine and BUN analysis as an indicator of kidney health.Alternatively animal survival is monitored over time. Compound can beadministered to animals before and/or after the surgery and the effectson serum creatinine, BUN or animal survival used as indicators ofcompound efficacy.

Mouse Model of Tumor Growth

C57BL/6 mice 6-16 weeks of age are injected subcutaneously with 1×105TC-1 cells (ATCC, VA) in the right or left rear flank. Beginning about 2weeks after cell injection, tumors are measured with calipers every 2-4d until the tumor size required the mice are killed. At the time ofsacrifice animals are subjected to a full necropsy and spleens andtumors removed. Excised tumors are measured and weighed. Compounds maybe administered before and/or after tumor injections, and a delay orinhibition of tumor growth used to assess compound efficacy.

In Table 3, below, structures and activity are provided forrepresentative compounds described herein. Activity is provided asfollows for the chemotaxis assay as described herein (Example 78 B 3):+, 500 nM≤IC₅₀; ++, 50 nM≤IC₅₀<500 nM; +++, 5 nM≤IC₅₀<50 nM; and ++++,IC₅₀<5 nM.

TABLE 3 Structure & Biological Activity of Specific Embodiments Mig IC50Compound Structure (nM) 1.001

+++ 1.002

+++ 1.003

++++ 1.004

+++ 1.005

++++ 1.006

+++ 1.007

++ 1.008

++++ 1.009

++ 1.010

+ 1.011

+ 1.012

++ 1.013

+++ 1.014

+++ 1.015

+++ 1.016

+ 1.017

+ 1.018

+++ 1.019

+++ 1.020

++++ 1.021

++ 1.022

++ 1.023

++++ 1.024

++++ 1.025

++ 1.026

+++ 1.027

+++ 1.028

+ 1.029

+++ 1.030

++++ 1.031

+++ 1.032

++++ 1.033

++ 1.034

+ 1.035

++++ 1.036

++++ 1.037

+++ 1.038

+++ 1.039

+++ 1.040

+++ 1.041

++++ 1.042

++ 1.043

+++ 1.044

++++ 1.045

++++ 1.046

++++ 1.047

++ 1.048

++++ 1.049

+++ 1.050

++++ 1.051

++++ 1.052

+++ 1.053

++++ 1.054

++++ 1.055

+++ 1.056

++++ 1.057

++++ 1.058

++++ 1.059

++++ 1.060

++++ 1.061

++++ 1.062

++++ 1.063

++++ 1.064

++ 1.065

++++ 1.066

++++ 1.067

+++ 1.068

+++ 1.069

++++ 1.070

++++ 1.071

++++ 1.072

+++ 1.073

++++ 1.074

++++ 1.075

++ 1.076

++++ 1.077

++++ 1.078

++++ 1.079

++ 1.080

++++ 1.081

++++ 1.082

+++ 1.083

+++ 1.084

++++ 1.085

++++ 1.086

++++ 1.087

+++ 1.088

++++ 1.089

+++ 1.090

+++ 1.091

+++ 1.092

++++ 1.093

++++ 1.094

++++ 1.095

++++ 1.096

++++ 1.097

+++ 1.098

++++ 1.099

++++ 1.100

++++ 1.101

++++ 1.102

+++ 1.103

+++ 1.104

++++ 1.105

+++ 1.106

++++ 1.107

+++ 1.108

+++ 1.109

++++ 1.110

+++ 1.111

+++ 1.112

+++ 1.113

++++ 1.114

+++ 1.115

++++ 1.116

+++ 1.117

+++ 1.118

+++ 1.119

+++ 1.120

+++ 1.121

+++ 1.122

+++ 1.123

++++ 1.124

+++ 1.125

++++ 1.126

++++ 1.127

++++ 1.128

++++ 1.129

++ 1.130

+++ 1.131

+++ 1.132

++++ 1.133

++++ 1.134

++ 1.135

++++ 1.136

++++ 1.137

++++ 1.138

++++ 1.139

++++ 1.140

++++ 1.141

++++ 1.142

++++ 1.143

++++ 1.144

++++ 1.145

++++ 1.146

++++ 1.147

++++ 1.148

++++ 1.149

+++ 1.150

++++ 1.151

++++ 1.152

++++ 1.153

+++ 1.154

+++ 1.155

+++ 1.156

++++ 1.157

++++ 1.158

++++ 1.159

++++ 1.160

++++ 1.161

++++ 1.162

+++ 1.163

++++ 1.164

++++ 1.165

++ 1.166

++ 1.167

++++ 1.168

++ 1.169

+++ 1.170

++++ 1.171

++++ 1.172

++++ 1.173

+++ 1.174

++++ 1.175

++++ 1.176

++++ 1.177

++++ 1.178

++ 1.179

++++ 1.180

++++ 1.181

++++ 1.182

+++ 1.183

+++ 1.184

++++ 1.185

++++ 1.186

++ 1.187

++++ 1.188

++++ 1.189

++ 1.190

+ 1.191

++ 1.192

+ 1.193

++ 1.194

++ 1.195

+++ 1.196

+++ 1.197

+++ 1.198

+++ 1.199

++++ 1.200

++++ 1.201

+++ 1.202

+++ 1.203

+++ 1.204

++ 1.205

+++ 1.206

+++ 1.207

+++ 1.208

++ 1.209

+++ 1.210

+++ 1.211

+++ 1.212

++++ 1.213

+++ 1.214

+++ 1.215

+ 1.216

+++ 1.217

++ 1.218

++++ 1.219

+++ 1.220

+++ 1.221

+++ 1.222

+++ 1.223

++++ 1.224

+ 1.225

+ 1.226

++++ 1.227

++++ 1.228

++ 1.229

+++ 1.230

++++ 1.231

++++ 1.232

++++ 1.233

++++ 1.234

+++ 1.235

++++ 1.236

++ 1.237

++++ 1.238

+++ 1.239

+++ 1.240

+++

While particular embodiments of this invention are described herein,upon reading the description, variations of the disclosed embodimentsmay become apparent to individuals working in the art, and it isexpected that those skilled artisans may employ such variations asappropriate. Accordingly, it is intended that the invention be practicedotherwise than as specifically described herein, and that the inventionincludes all modifications and equivalents of the subject matter recitedin the claims appended hereto as permitted by applicable law. Moreover,any combination of the above-described elements in all possiblevariations thereof is encompassed by the invention unless otherwiseindicated herein or otherwise clearly contradicted by context.

All publications, patent applications, accession numbers, and otherreferences cited in this specification are herein incorporated byreference as if each individual publication or patent application werespecifically and individually indicated to be incorporated by reference.

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein, ring vertex A⁰is NH or C(O); each of ring vertices A¹ and A³ are independentlyselected from the group consisting of N, NH, CH, C(O) and C(R⁴); each ofring vertices A², A⁵ and A⁶ is independently selected from the groupconsisting of N, CH, and C(R⁴); ring vertex A⁴ is selected from thegroup consisting of N, N(C₁₋₄ alkyl), CH, and C(R⁴); and no more thantwo of A³, A⁴, A⁵ and A⁶ are N; each of the dashed bonds independentlyis a single or double bond; R¹ is selected from the group consisting ofheteroaryl, C₆₋₁₀ aryl, —C₁₋₈ alkylene-heteroaryl, —C₁₋₈alkylene-C₆₋₁₀aryl, C₃₋₈ cycloalkyl, four to eight membered heterocycloalkyl, C₁₋₈alkyl, C₁₋₈ haloalkyl, —C(O)NR^(1a)R^(1b), and —CO₂R^(1a); wherein theheterocycloalkyl group is a 4 to 8 membered ring having from 1 to 3heteroatoms as ring vertices selected from N, O and S; the heteroarylgroup is a 5 to 10 membered aromatic ring having from 1 to 3 heteroatomsas ring vertices selected from N, O and S; wherein R^(1a) and R^(1b) areeach independently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₆₋₁₀ aryl, and —C₁₋₆ alkylene-C₆₋₁₀ aryl; wherein R¹ isoptionally substituted with 1 to 5 R⁵ substituents; R^(2a) and R^(2e)are each independently selected from the group consisting of C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-S—C₁₋₆ alkyl, CN, and halogen; R^(2b),R^(2c), and R^(2d) are each independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-S—C₁₋₆alkyl, cyano, and halogen; each R³ is independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl and hydroxyl, andoptionally two R³ groups on the same carbon atom are combined to formoxo (═O); each R⁴ is independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, —O—C₁₋₆ haloalkyl, halogen, cyano, hydroxyl, —S—C₁₋₆ alkyl,—C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-S—C₁₋₆ alkyl, —NR^(4a)R^(4b),—CONR^(4a)R^(4b), —CO₂R^(4a), —COR^(4a), —OC(O)NR^(4a)R^(4b),—NR^(4a)C(O)R^(4b), —NR^(4a)C(O)₂R^(4b), and —NR^(4a)—C(O)NR^(4a)R^(4b);each R^(4a) and R^(4b) is independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; each R⁵ isindependently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈alkoxy, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₁₋₈ hydroxyalkyl, —C₁₋₈alkyl-heterocycloalkyl, —C₁₋₈ alkyl-C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl,heterocycloalkyl, halogen, OH, C₂₋₈ alkenyl, C₂₋₈ alkynyl, CN,C(O)R^(5a), —NR^(5b)C(O)R^(5a), —CONR^(5a)R^(5b), —NR^(5a)R^(5b), —C₁₋₈alkylene-NR^(5a)R^(5b), —S—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆alkyl-S—C1.6 alkyl, —OC(O)NR^(5a)R^(5b), —NR^(5a)C(O)₂R^(5b),—NR^(5a)—C(O)NR^(5b)R^(5b) and CO₂R^(5a); wherein wherein theheterocycloalkyl group is a 4 to 8 membered ring having from 1 to 3heteroatoms as ring vertices selected from N, O and S; wherein eachR^(5a) and R^(5b) is independently selected from the group consisting ofhydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl, or when attached to the samenitrogen atom R^(5a) and R^(5b) are combined with the nitrogen atom toform a five or six-membered ring having from 0 to 1 additionalheteroatoms as ring vertices selected from N, O, or S; and the subscriptn is 0, 1, 2 or
 3. 2. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the ring portion having A⁰, A¹, A², A³,A⁴, A⁵, and A⁶ as ring vertices is a bicyclic heteroaryl selected fromthe group consisting of

wherein m is 0, 1, 2 or 3; and wherein the R⁴ substituents, whenpresent, are attached to any suitable carbon ring vertex of the bicyclicheteroaryl.
 3. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein the ring portion having A⁰, A¹, A², A³, A⁴, A⁵,and A⁶ as ring vertices is selected from the group consisting of

wherein m is 0, 1, 2, or
 3. 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R⁴ isindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₄ haloalkyl, halogen, cyano, hydroxyl,—NH₂, —CONR^(4a)R^(4b), and —CO₂R^(4a); and wherein the R⁴ substituents,when present, are attached to any suitable carbon ring vertex of thebicyclic heteroaryl.
 5. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the ring portion having A⁰, A¹, A², A³,A⁴, A⁵ and A⁶ as ring vertices is selected from the group consisting of:


6. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is selected from the group consisting of heteroaryl,C₆₋₁₀ aryl, —C₁₋₆ alkylene-heteroaryl, —C₁₋₆ alkylene-C₆₋₁₀ aryl, fourto eight membered heterocycloalkyl, C₃₋₈ cycloalkyl, C₁₋₈ alkyl,—C(O)NR^(1a)R^(1b), and —CO₂R^(1a), wherein the heteroaryl group is a 5or 6 membered aromatic ring having from 1 to 3 heteroatoms as ringvertices selected from N, O and S, and R¹ is optionally substituted with1 to 3 R⁵ substituents.
 7. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is selected fromthe group consisting of pyridyl, pyrimidyl, pyrazinyl, thiadiazolyl,phenyl, benzyl, cyclopentyl, tetrahydropyranyl, —C(O)NR^(1a)R^(1b),—CO₂R^(1a), and C₁₋₈ alkyl, wherein R¹ is optionally substituted with 1to 3 R⁵ substituents.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

each of which is optionally substituted with 1 or 2 R⁵ substituents. 9.The compound of claim 8, wherein each R⁵ is independently selected fromthe group consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₁₋₈haloalkoxy, C₁₋₈ hydroxyalkyl, —C₁₋₈ alkyl-heterocycloalkyl, C₃₋₆cycloalkyl, halogen, —CONR^(5a)R^(5b), —NR^(5a)R^(5b), —C₁₋₈alkylene-NR^(5a)R^(5b), and —CO₂R^(5a), each R^(5a) and R^(5b) isindependently selected from the group consisting of hydrogen and C₁₋₄alkyl, or when attached to the same nitrogen atom can be combined withthe nitrogen atom to form a 5 or 6-membered ring; and theheterocycloalkyl group is a 4 to 6 membered ring having from 1 to 3heteroatoms as ring vertices selected from N, O and S.
 10. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ isselected from the group consisting of


11. The compound of claim 10, wherein each R⁵ is independently selectedfrom the group consisting of cyclopropyl, isopropyl, isopropyloxy, OMe,Me, Cl, F, —CONH₂, —CF₃, —O—CF₃,


12. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is selected from the group consisting of:

each of which is optionally substituted with 1 to 2 R⁵ substituents. 13.The compound of claim 12, wherein each R⁵ is independently selected fromthe group consisting of halogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, and C₂₋₈ alkenyl.
 14. The compound of claim 13, wherein eachR⁵ is independently selected from the group consisting of Cl, F, Me,isopropyl, —CF₃, cyclopropyl, and isopropenyl.
 15. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom the group consisting of


16. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is


17. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(2b), R^(2c), and R^(2d) are each H.
 18. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, whereinR^(2a) and R^(2e) are each independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆haloalkyl, and halogen.
 19. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(2a) and R^(2e) areeach independently selected from the group consisting of Me, Et, F, Cl,OMe, OCF₃, and


20. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein

is selected from the group consisting of


21. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein n is
 0. 22. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein n is 2 and the two R³groups are on the same carbon atom and are combined to form oxo (═O).23. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein


24. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having a structure represented by Formula (Ia), or (Ib):


25. The compound of claim 2, or a pharmaceutically acceptable saltthereof, having a structure represented by Formula (Ic), (Id), or (Ie):

wherein m is 0, 1 or 2 and wherein the R⁴ substituents may be attachedto any suitable carbon ring vertex of the bicyclic heteroaryl.
 26. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,having a structure represented by Formula (If), (Ig), (Ih), and (Ii):

wherein p is 0, 1 or
 2. 27. The compound of claim 24, or apharmaceutically acceptable salt thereof, wherein R^(2a) and R^(2e) areboth ethyl.
 28. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, having a structure represented by Formula (Ik),(Il), or (Im):

wherein p is 0, 1 or 2, m is 0, 1 or 2 and wherein the R⁴ substituentsmay be attached to any suitable carbon ring vertex of the bicyclicheteroaryl.
 29. The compound of claim 28, or a pharmaceuticallyacceptable salt thereof, wherein p is 1 or 2; m is 1 or 2; each R⁵ isindependently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈alkoxy, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₁₋₈ hydroxyalkyl, —C₁₋₈alkyl-heterocycloalkyl, C₃₋₆ cycloalkyl, halogen, —CONR^(5a)R^(5b),—NR^(5a)R^(5b), and —C₁₋₈ alkylene-NR^(5a)R^(5b), wherein each R^(5a)and R^(5b) is independently selected from the group consisting ofhydrogen and C₁₋₄ alkyl, or when attached to the same nitrogen atom canbe combined with the nitrogen atom to form a 5 or 6-membered ring,wherein the heterocycloalkyl group is a 4 to 6 membered ring having from1 to 3 heteroatoms as ring vertices selected from N, O, and S; and eachR⁴ is independently selected from the group consisting of C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₄ haloalkyl, halogen, cyano,hydroxyl, —NH₂, —CONR^(4a)R^(4b), and —CO₂R^(4a).
 30. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein saidcompound is selected from the group in Table 3 having ++ or +++activity.
 31. A pharmaceutical composition comprising a compound ofclaim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.